Behavioral & Cognitive Disorders
Fragile X syndrome
Nov. 21, 2022
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In this article, the author reviews developments in neurodegeneration and brain iron accumulation (NBIA). The previous extensive contributions of Schiffmann and Swaiman regarding neurodegeneration and brain iron accumulation (formerly known as Hallervorden-Spatz syndrome) and the childhood differential diagnosis have been extended to adults by genetic studies of pantothenate kinase 2 (PANK2). Phenotypes of PANK2 are variable, with many later onset cases or others with slower progression due to differences in inherited kinase function. Several other additional uncommon inherited diseases affecting brain iron metabolism have been discovered in addition to PANK2, which are also associated with brain iron accumulation: PLA2G6 associated neurodegeneration, neuroferritinopathy, and aceruloplasminemia. Much smaller amounts of iron accumulation have also been associated with neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and multiple sclerosis. Neurodegeneration with brain iron accumulation may encompass a larger number of disorders.
Pantothenate kinase-associated neurodegeneration (PKAN) was discovered in 1922. Several reports have discussed Julius Hallervorden's unethical scientific activities during World War II (78; 77). As a result, pantothenate kinase-associated neurodegeneration and neurodegeneration with brain iron accumulation type 1 (NBIA type 1) have replaced the Hallervorden-Spatz eponym (19; 55; 27). Since discovery of the gene for pantothenate kinase 2 as a cause of the classic young onset neurodegeneration with brain iron accumulation type 1 syndrome (100), it has been shown that a significant number of cases of less typical and later onset disease lack the gene or have a genetic mutation resulting in lesser defects in the enzyme (27; 89; 26). The term neurodegeneration with brain iron accumulation type 1 (NBIA-1) has also been in use as an alternative name for HSS for some time. The NBIA family of disorders also includes PLA2G6 associated neurodegeneration (PLAN), neuroferritinopathy (15; 11), and aceruloplasminemia (40). Brain iron accumulation may also be present in common neurodegenerative disorders such as multiple sclerosis (06) and Alzheimer and Parkinson diseases (68; 99; 23; 70).
In the original report, the prominent pathologic characteristics associated with a presumably consistent clinical pattern were described. Since then, a spectrum of conditions included under this designation have been reported, detailed, and rearranged in order to provide useful subclassifications. The massive iron deposition in the globus pallidus and substantia nigra, the autosomal recessive genetic transmission, and the clinical manifestations (80) generally set apart the classic form of pantothenate kinase-associated neurodegeneration from other neurodegenerative and extrapyramidal conditions. The classic phenotypic features of pantothenate kinase-associated neurodegeneration include early onset and rapidly progressive disease. The atypical presentations include later onset in the second or third decade, slower progression and speech and psychiatric disorders along with the extrapyramidal and corticospinal tract features of the classic form (32; 27).
After many years of efforts to find a specific gene abnormality, the gene PANK2 was found to be defective in some patients with neurodegeneration with brain iron accumulation type 1 (100a). The defective gene results in the deficiency of the enzyme pantothenate kinase. All of the patients with the typical classic form and one-third of the patients with an atypical form of the disease were found to have mutations in PANK2 (27). A genotyping study of 72 patients with clinical profiles of PKAN syndrome of NBIA and MR imaging revealed PANK2 mutations in 48, but none were found in 24 other cases. Of the 72, 17 were atypical as their onset was in the second or third decade of life. For 7 of the 24 PANK2-negative cases, onset was in the first decade (26). As in other studies, clinical phenotypes of patients without PANK2 deficiency featured dystonia, corticospinal tract abnormalities and cognitive decline. More studies (58; 26) found that up to 90% of PKAN patients had spasticity and cognitive decline compared to 30% reported by Hayflick and colleagues (27).
The initial case report consisted of members of a family of 12 children. Three children died in infancy, and 4 were in good health. The remaining 5, all girls, manifested clinical involvement between 7 years and 9 years of age. Initial symptoms were predominantly those of gait difficulties associated with rigidity of the legs and deformity of the feet. In retrospect, the findings were consistent with dystonia. The girls manifested progressive intellectual loss and dysarthria. Two developed atrophy of the distal muscles, and 1 experienced corticospinal tract impairment. Each girl of a pair of twins exhibited gray-brown skin pigmentation. One of the girls experienced increased muscle tone of the neck (presumably dystonia), swallowing difficulties, and choreoathetotic movements. The girls all died between the ages of 16 years and 27 years (96). Gross rust-brown pigmentation of the globus pallidus and the zona reticulata of the substantia nigra were evident during neuropathologic study.
Subsequently, 3 brothers were reported who developed athetotic movements, tremors, visual difficulties associated with optic atrophy, and corticospinal tract findings at 9 years to 10 years of age (36). The oldest boy died at age 26 years with similar findings on neuropathology.
A number of other cases were reported (96), including a case by Messing, suggesting that the diagnosis could be made in the presence of intellectual deterioration, extrapyramidal movement disorder, and optic atrophy (49; 50). Through the years, familial cases were reported with more or less parallel clinical and neuropathologic findings to the original patients of Hallervorden and Spatz.
A number of new genes have been found, including PLA2G6, FAHN, C19ORF12, ATP13A2, FTL, CP, DCAF17, and COASY (21). Their phenotypes will be outlined in the next section.
This 28-year-old woman presented at 11 years of age with toe walking. She has mild intellectual impairment, emotional difficulties, and anger control problems; severe hypokinetic dysarthria, hypophonia, and drooling; marked bra...
In a review, Dooling and associates summarized the clinical features and postmortem examinations of 54 individuals with neurodegeneration with brain iron accumulation (16). The most common features of the core group (42 of 64 patients) included the following: (1) occurrence at a young age, generally after earliest childhood; (2) a motor disorder, mainly of extrapyramidal type, characterized by dystonic postures, muscular rigidity, involuntary movements of choreoathetoid or tremulous type, but with the findings suggesting corticospinal tract dysfunction as well; (3) mental changes indicative of dementia; and (4) a relentless, progressive course extending over several years, leading to death in early adulthood.
Familial involvement was present in approximately one-half of the core group patients. In the sporadic cases, 15% of the patients were the result of consanguineous relationships. In another group, the clinical features were similar to the abnormalities in the large core group, but the pathologic changes did not extend to the pars reticulata of the substantia nigra. In the smallest group, the neuropathologic findings were similar to the initial case report, but the clinical pattern varied considerably.
Gait difficulties or postural abnormalities were the initial manifestations in 37 of the 42 patients. Other presenting complaints included intellectual impairment in 4 patients, and visual difficulties in 1 patient, as the result of retinal degeneration.
The prototypic course included the progression of rigidity and the presence and progression of postural abnormalities, usually in the form of dystonia (23 of 42 patients); 19 of the patients had choreoathetosis. Tremor was present in 15 of the 42 patients. Dysarthria was universal. Spasticity or hyperreflexia, usually with extensor plantar responses was present in 28 of the 42 patients. Although progressive intellectual degeneration was common, 7 patients did not manifest mental impairment; 9 patients were reported to have mental retardation. Seizures occurred in 9 of the 42 patients. Retinitis pigmentosa was present in 11 patients.
Clinical manifestations of neurodegeneration with brain iron accumulation type 1 patients vary from patient to patient. The classic form is characterized by onset in the mid or late portion of the first decade of life, and the presence of corticospinal tract involvement (eg, spasticity, hyperactive deep tendon reflexes, clonus, and extensor toe signs). Signs and symptoms of extrapyramidal dysfunction may be delayed for several years and usually occur in the form of dystonia; however, rigidity, choreoathetosis, and tremor also may be present. Intellectual retardation or decline is present in most patients. Optic atrophy is also a common feature and is often accompanied by retinitis pigmentosa. Tongue protrusion dystonia was reported in 3 childhood onset cases (64).
Although progression to death at least by early adulthood is described, it has become obvious that the clinical course is variable. Some patients undergo slowly progressive changes, or even plateau for many years and continue to function in their third decade of life. Other patients undergo rapid deterioration with profound dystonia and rigidity, difficulty chewing and swallowing, and respiratory compromise; they die within a year or 2 years after onset of the first symptoms.
The classification of pantothenate kinase-associated neurodegeneration syndromes can be developed by use of age of onset and course criteria. In view of the fact that general clinical classification of conditions with known enzymatic deficiencies (leukodystrophies) remains problematic, it seems reasonable to attempt classification before gene evaluation is undertaken. The early experience with gene testing indicates a wider spectrum of clinical manifestations in the syndrome than previously appreciated.
The delineation of certain pantothenate kinase-associated neurodegeneration types is as follows:
(1) Early-onset childhood types of PKAN (those with a diagnosis evident before 10 years of age).
(1a) Rapidly progressive.
(2) Late-onset types of PKAN (those with a diagnosis evident after 10 years and before 18 years of age) are slowly progressive.
(3) Adult types of PKAN syndrome are also slowly progressive.
The rapidly progressive early-onset childhood type usually manifests nonspecific motor difficulties suggestive of spasticity over several years, and then with severe movement difficulties that progress rapidly, and often incapacitate the patient in less than a year; abnormal movements usually include dystonia, rigidity, and spasticity. Severe opisthotonos is often a prominent finding. The degree of restriction of movement because of posturing may impair both respiration and feeding. In addition, some of these patients will have associated acanthocytosis in their peripheral blood smears. Most of these patients develop difficulties between 5 and 8 years of age.
The slowly progressive early-onset childhood type may manifest as early as 1 year of age; however, the majority of these patients become symptomatic after age 5 years. This group constitutes the largest pantothenate kinase-associated neurodegeneration group, numerically. They present in a number of ways; however, movement disorders, particularly dystonia, are most common. Only after further study does it become evident that optic atrophy, retinitis pigmentosa, and sometimes, intellectual loss are present. The presence of intellectual impairment or dementia is not uniformly evident. The MRI findings have greatly accelerated diagnosis in recent years. All T2-weighted brain MRIs of patients with pantothenate kinase-associated neurodegeneration, whether classic or atypical, show a specific pattern of “the eye of the tiger sign” (hyperintensity within the hypointense medial globus pallidus) (75; 22; 27). This pattern was not seen in any patients without mutations in that study (27). In a study of patients with neurodegeneration and brain iron accumulation selected by MRI and movement disorders, a third showed no abnormality in pantothenate kinase on genotyping (26). The hypointensity of the globus pallidus on MR is attributed to iron accumulation, whereas the central hyperintensity probably reflects an increase in the water signal due to vacuolization of the tissue (66). Although the MRI sign of the “eye of the tiger” is important in the clinical diagnosis of and characteristic of pantothenate kinase deficiency, it is not specific to that disease. A diffuse hyperintense region within the globus pallidus is often seen in normal elderly adult brains using 3 tesla MRI although the hypointense rim is usually less striking than in the classical eye-of-the-tiger finding (Schenck and Zimmerman, unpublished). MRI changes may precede clinical symptoms (29) and the central hyperintensity in the globus pallidus may also precede surrounding hypointensity as the disease progresses suggesting that iron accumulation is a secondary phenomenon in the pathogenesis of pantothenate kinase 2 disease (28).Many of these patients will continue for many years in pursuit of educational goals despite their ongoing general motor and articulation difficulties.
The late-onset childhood type usually progresses even slower than the slowly progressive early-onset childhood type. The progression of the condition may appear to be so slow that the patient may appear to have reached a plateau, particularly after effective medication to ameliorate movement symptoms, and spasticity has been administered. Complaints related to dystonia, including articulation difficulties, will be most prominent. Muscle cramping associated with the dystonia will emerge as a complaint. Gait impairment may progress and prove to be the major handicap. Although these patients may or may not lose intellectual capabilities, sophisticated psychometric testing often reveals learning disabilities. A history of academic difficulties may be obtained from many of these patients; however, it is not uncommon for these patients to continue significant educational pursuits.
The adult type is much less common. Movement disorders predominate and are more varied than in the early-onset types. At times athetosis, chorea, and myoclonus may predominate; nevertheless, dystonia is the most frequently associated movement disorder.
Atypical adult forms of parkinsonism may be related to Hallervorden-Spatz syndrome (90), and some may simulate amyotrophic lateral sclerosis (94). Diagnosis by MRI may be overlooked because of the natural increase in iron accumulation in the globus pallidus and substantia nigra with maturation. Nevertheless, the MRI findings are usually discernible if the diagnosis is suspected.
Patients with atypical parkinsonism may have clinical, radiologic, and pathologic characteristics of neurodegeneration with brain iron accumulation (26), and some have PKAN (89). These findings may include mental retardation, tremor, and levodopa-responsive parkinsonism. Hallucinations and dementia may follow. Brain MRI may demonstrate iron deposition in the globus pallidus, the substantia nigra, and the pulvinar of the thalamus (90). Some of these cases of atypical parkinsonism or dystonia have been shown on rare occasion to be due to neuroferritinopathy (11). Some cases of aceruloplasminemia also have parkinsonism (40).
Pantothenate kinase-associated neurodegeneration appears to be the most common of the inherited disorders of brain iron accumulation with more than 100 genetically proven cases in the United States (27) and Germany (26). Aceruloplasminemia was initially described in Japan in 1987 by Miyajima and colleagues (51) and appears to be more common in that country with more than 40 families known. We are aware of only a few cases in the Britain and the United States (18; 70). The genetic defect was described in 1995. Like PANK, it is a recessive disorder. Brain iron accumulation is extensive in aceruoloplasminemia (aCp) and includes white matter as well as deep gray (40; 69) even more extensive than in PANK and is more than 3 standard deviations above the amount found in normal aging brain (70). The clinical symptoms of aCp develop later in life than PANK and include diabetes mellitus (not seen in PANK) retinal degeneration and movement disorders including parkinsonism, cerebellar ataxia and dementia. MRI shows great accumulations of iron in the liver and in extensive regions of the brain. Iron deposition is particularly prominent in the caudate and the putamen.
Neuroferritinopathy. Neuroferritinopathy is an autosomal dominant disease due to a mutation in the gene encoding ferritin light polypeptide and has been reported in 30 English cases (15) and 7 from a French family. This is an adult onset basal ganglia disorder more often characterized by dystonia or by chorea or bradykinesia or some combination of the 3 symptoms. An early onset case at age 13 with a gait disorder was reported due to a missense mutation in the ferritin light chain (45). Although there is an accumulation of iron on MRI (Short T2), especially in the red nucleus and basal ganglia, there is a striking cavitation of the basal ganglia seen as a large area of high signal in the globus pallidus, much more so than seen in the “eye of the tiger” in PANK (15). Clinically, this disease can be confused in some cases with hereditary dystonia (DTY). Usually there is a low serum ferritin. This disease is associated with intracellular accumulation of iron containing granules in brain (15), and other body tissues and muscle biopsy can be used for diagnosis (72).
Although uncommon, these 3 metabolic disorders of iron metabolism provide insights into normal iron management and abnormalities that can cause or participate in neurodegeneration of the nervous system, and for that matter other organs such as the eye in pantothenate kinase-associated neurodegeneration and aCp, and the pancreas in the latter. They clearly show that iron can cause neurodegeneration when some aspect of its complex metabolism is disordered. Further evidence is provided from mice in which the iron regulatory protein-2 has been knocked out. They develop neurodegeneration and iron accumulation (43).
Aceruloplasminemia (CP gene, autosomal recessive inheritance). Aceruloplasminemia is the most striking of these human disorders in terms of iron accumulation and it is a wonder they do relatively well with later onset and slow disease with so much of it. Neurologic symptoms of aceruloplasminemia may not appear until the fifth decade. Ceruloplasmin is a copper-containing enzyme whose main function is to serve as a ferroxidase converting iron from its ferrous (valence 2) to ferric (valence 3) states. Iron must be in the ferric state to be loaded onto transferrin. Furthermore, brain ceruloplasmin is produced in astrocytes in the brain and the systemic form is made in the liver. The lack of ceruloplasmin results in intracellular iron accumulation (21).
In neuroferritinopathy, ferritin is defective and results in inadequate storage and release of iron. Exactly how this results in neurodegeneration is not presently totally known. Deficiency in pantothenate kinase results in an accumulation of cysteine, which is thought to rapidly oxidize and results in free-radical production and excess lipid peroxidation (04). Mutant pantothenate kinase 2 in PKAN was shown to be a mitochondrial form of the enzyme resulting in loss of function of the enzyme and altered mitochondrial lipid metabolism.
PLAN (PLA2G6 associated neurodegeneration), autosomal recessive inheritance. Gene defect encoding a phospholipase A was found in some cases of infantile neuroaxonal dystrophy many of which had iron accumulation by MRI and the related Karak syndrome family (53). This gene is also found in adult onset dystonia parkinsonism, which typically does not have the eye-of-the-tiger sign on MRI. Patients with PLAN may have T2 hypointensity in globus pallidus without hyperintensity (71). There is also an intermediate form named atypical NAD with childhood onset, dystonia, spastic quadriparesis, and speech delay (21).
MPAN (mitochondrial membrane protein-associated neurodegeneration) C19ORF12 gene, autosomal recessive inheritance. This disorder manifests with developmental delay followed by adolescent or adult onset dystonia, parkinsonism, and dementia (21). Spasticity is common in childhood onset cases whereas adults may have more prominent dysphagia, bowel, and bladder dysfunction (65). A case series of 17 patients with MPAN from Russia included a case with severe muscle weakness without spasticity or optic atrophy (79).
Kufor Rakeb syndrome (ATP13A2/PARK9), autosomal recessive inheritance. This disorder is characterized mainly by juvenile onset dystonia, parkinsonism, and dementia (14).
BPAN (beta-propeller protein-associated neurodegeneration) WDR45 gene, X-linked dominant inheritance. BPAN typically presents as 2 forms. There is a childhood onset form with developmental delay, epilepsy, sleep disorder, and childhood onset rapidly progressive parkinsonism, dystonia, and dementia (65). For example, a 6-year-old patient with global developmental delay and epileptic encephalopathy was reported (09).The second one consists of developmental delay with autistic features in childhood, followed by dystonia, parkinsonism, and dementia at ages 20- to 30-years-old, also called static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) syndrome (95). Imaging of the SENDA phenotype shows hyperintense signal of the substantia nigra with a central band of hypointense signal in brain MRI (65).
FAHN (fatty acid hydroxylase-associated neurodegeneration) FA2H gene, autosomal recessive inheritance. Imaging findings include hypointensity of globus pallidus and significant pontocerebellar atrophy. Clinical features may include childhood onset dysmetria and falls, followed by progressive worsening of cerebellar features into adulthood with progressive spastic quadriplegia and dysphagia (42).
CoPAN (coenzyme A synthase protein-associated neurodegeneration/COASY protein-associated neurodegeneration) COASY gene, autosomal recessive inheritance. Features of the disorder include eye-of-the-tiger sign on MRI, spastic paraparesis, and parkinsonism. There may also be calcifications on CT head (41).
Woodhouse-Sakati syndrome (DCAF17 gene), autosomal recessive inheritance. Clinical features include associated hypogonadism, alopecia, and diabetes mellitus, in addition to generalized dystonia (97; 31).
In the core group of 42 patients, 24 patients were ill before age 10 years; 34 patients before age 15 years; and 39 patients by age 22 years. Three patients had unusually late onset. The mean duration of the disease was 11 years; 19 of the patients were dead by age 20 years; 32 patients by age 25 years; and 37 patients by age 35 years.
The specific etiology of neurodegeneration with brain iron accumulation is a genetic defect (100). Present data suggest that more than half of those with neurodegeneration with brain iron accumulation have PANK2 gene defect (27; 26). Patients with the classic syndrome (early onset) had the gene defect, whereas only one-third with late onset (atypical syndrome) had it in the report by Hayflick and colleagues (27). The study by Hartig and colleagues, in which studied patients selected by MR and movement disorders, detected a defect in PANK2 in 65% (26). Patients with loss of function alleles showed early onset; age of onset related to residual activity of pantothenate kinase in those with missense mutations that were more common. A novel nonsense mutation in PANK2 gene (c.T936A [p.C312X]) was found in 2 early-onset cases in Iran (20).
The mechanism whereby pantothenate kinase deficiency leads to clinical phenotype is not fully elucidated at this time. The enzyme is an essential regulatory enzyme in coenzyme A biosynthesis (100). It is hypothesized that this defect leads to CoA deficiency and a range of metabolic consequences, the most relevant of which are energy and lipid dyshomeostasis. Altered neuronal mitochondrial function plays an important role as the type of pantothenate kinase, which is altered in this disease is located in the neuronal mitochondria. Much is known about iron metabolism in brain; however, new information will be necessary to link the new genetic finding with known features of brain iron metabolism (08; 12; 62; 99; 04). Overall, the neuroinflammation in neurodegeneration with brain iron accumulation family of disorders involves genes involved with mitochondrial function (PANK, COASY, C19ORF12), phospholipid membrane synthesis (PLA2G6 and FA2H), autophagosomes (WDR45), lysosomes (ATP13A2), and iron metabolism (FTL and CP) (34).
The neurophysiologic causes of most of the signs and symptoms of PKAN are undoubtedly related to basal ganglia abnormalities. Most likely the degeneration of basal ganglia output neurons results in these clinical changes (52).
The rust-brown pigmentation evident on gross examination of the globus pallidus and the zona reticulata of the substantia nigra, documented in the original descriptions, remain the most unique neuropathologic characteristics of PKAN. Microscopically, iron granules were located in large astrocytes, microglial cells, and neurons. Some iron was located extracellularly, sometimes surrounding blood vessels. Unusual mulberry concretions were found free in the tissue and prominently stained with hematoxylin. Increased population of glial cells, some with large, pale nuclei were found in the globus pallidus. Furthermore, unusual, round structures of various diameters, sometimes larger than neurons, were demonstrated with axonal stains. In the globus pallidus and zona reticulata, these peculiar structures were encircled by glial cells and contained pigment granules. Similar structures were distributed throughout the white and gray matter of the cerebrum, particularly in the subthalamic nucleus of Luys. These structures have become known as spheroid bodies.
In a report it has been proposed that a primary axonal disorder allows the seepage of iron into the axoplasm. Furthermore, it has been postulated that although iron may contribute to the axonal disease, accumulation of iron may be an epiphenomenon (38).
It is noteworthy that areas of the globus pallidus and the pars reticulata of the substantia nigra are relatively high in iron content in normal individuals (24); however, in PKAN, iron-containing pigment accumulates to an extraordinary degree in these areas. Myelin is decreased in the globus pallidus, and widely disseminated focal axonal swellings are located in the cerebral cortex and the pallidonigral system. Spheroids, which are posited to represent swollen axons, exist in large numbers in disrupted areas. Attempts at more precise characterization of spheroid bodies have been unsuccessful. Rabinowicz and Wildi suggested parallels between spheroid bodies and those found by Seitelberger in neuroaxonal dystrophy (74; 73; 59). In neuroaxonal dystrophy, lipid material accumulates in the pallidum, but no pigments. Nevertheless, primarily on neuropathologic grounds, the suggestion was made by Seitelberger that neuroaxonal dystrophic patients had infantile and late-infantile types of Hallervorden-Spatz syndrome. Although the axonal pathology that results in spheroid formation is similar to the alterations in infantile neuroaxonal dystrophy, there is no established clinical or genetic association between these 2 groups of patients. Current evidence strongly suggests that infantile neuroaxonal dystrophy differs from Hallervorden-Spatz syndrome because of different ultrastructural features and immunoreactivity pattern of cytoskeletal components. An immunohistochemical and ultrastructural analysis of dystrophic axons in the brain and peripheral nerve of a patient with familial infantile neuroaxonal dystrophy revealed prevalent membrano-tubular or granulo-vesicular profiles with a graded pattern of evolution in infantile neuroaxonal dystrophy. In the brain of a patient with familial neurodegeneration with brain iron accumulation, dense bodies, vesicles, and amorphous material were present. Dystrophic axon immunoreactivity with tai-protein and 200-kd neurofilament antibodies was more positive in neurodegeneration with brain iron accumulation than in infantile neuroaxonal dystrophy (47). Tau pathology was the predominant abnormality in a study of a sporadic late onset case of the syndrome (98).
Two patients with neurodegeneration with brain iron accumulation were reported who had increased creatine kinase serum activity. Subsequent biopsies revealed myopathic signs such as subsarcolemmal accumulation of myeloid structures, dense bodies and debris, endomysial macrophage activation, focal necrosis, and fiber splitting (46).
Intraneuronal and extraneuronal deposition of ceroid-lipofuscin is usually evident, and is likely the result of peroxidation of lipids in the affected regions. It has also been proposed that neuromelanin accumulation in these areas is a natural progression of degradation of ceroid-lipofuscin (57).
It is reasonable to conclude that the neuropathologic changes that form a distinctive pattern (16; 57) consist of (1) asymmetric, partially destructive lesion of the globus pallidus, especially the internal segment, and the pars reticulata of the substantia nigra characterized by some loss of myelinated fibers and neurons, with gliosis; (2) widely disseminated, rounded, or oval nonnucleated structures (spheroids) identifiable as swollen axons, especially numerous in the regions indicated as the site of destructive changes, but not confined to these areas; and (3) accumulations of pigment, much of it iron-containing, as well as some in the form of ceroid-lipofuscin and neuromelanin, in the regions chiefly affected.
The variation in clinical symptomatology suggests that there are several conditions that are genetically separate or represent allelic variants. It is likely that several conditions are subsumed under classification of neurodegeneration with brain iron accumulation; therefore, it is possible that various forms of the disease are inherited because of different alleles on 1 gene locus, or there may be more than 1 locus, which may involve another gene or genes. A study suggests locus heterogeneity (26). When a familial incidence is present, the condition appears to be inherited as an autosomal recessive condition. Consanguinity, in some instances, and apparent sporadic occurrence of neurodegeneration with brain iron accumulation is corroborative of autosomal recessive inheritance.
A primary genome scan was performed using samples from a large, consanguineous family (neurodegeneration with brain iron accumulation type 1). Although this family was immensely powerful for mapping, the region demonstrating homozygosity in all affected members spans only 4 cm, requiring close markers in order to detect linkage. Neurodegeneration with brain iron accumulation gene maps to an interval flanked by D20S906 and D20S116 on chromosome 20p12.3-p13. Linkage was confirmed in 9 additional families of diverse ethnic backgrounds. It is of great interest that some patients who appear to have phenotypic neurodegeneration with brain iron accumulation were found not to have this particular gene abnormality (87; 26).
The epidemiology is unknown.
Genetic counseling is now possible. The availability of genetic screening will facilitate counseling.
The development of MRI has increased the number of clinical and pathological reports of pantothenate kinase-associated neurodegeneration. The variability among patients is considerable. For purposes of classification, prognosis, study of gene loci, and investigation of basic pathogenetic mechanisms, it is necessary that comparable patients be grouped and studied (25).
A profile of the most frequent clinical characteristics of pantothenate kinase-associated neurodegeneration can be developed. Furthermore, certain features should exclude the diagnosis. All of the obligate features, and no fewer than 2 of the corroborative features, should be present. None of the exclusionary features should be present.
The obligate features of pantothenate kinase-associated neurodegeneration are onset during the first 2 decades of life: progression of signs and symptoms, and evidence of extrapyramidal dysfunction, including 1 or more of the following: dystonia, rigidity, and choreoathetosis. The corroborative features are corticospinal tract involvement-spasticity or extensor toe signs, progressive intellectual impairment, retinitis pigmentosa or optic atrophy (usually associated visual evoked response-electroretinogram abnormalities, positive family history consistent with autosomal recessive inheritance, hypointense areas on MRI involving the basal ganglia, particularly the substantia nigra (most obvious in children during the first decade of life), and abnormal cytosomes in circulating lymphocytes or sea-blue histiocytes in bone marrow.
• Abnormal ceruloplasmin levels or abnormalities in copper metabolism.
• The presence of overt neuronal ceroid-lipofuscinosis, as demonstrated by severe visual impairment or difficult-to-control seizures, often of the generalized type (ie, atypical absence, generalized tonic-clonic).
• Predominant epileptic symptomatology.
• Severe retinal degeneration or visual impairment preceding other symptoms.
• Presence of familial history of Huntington chorea or other autosomal dominantly inherited neuromovement disorder.
• Presence of caudate atrophy as demonstrated by imaging studies
• A deficiency of hexosaminidase A.
• A deficiency of G(M1)- ganglioside beta-galactosidase.
• Nonprogressive course.
• Absence of extrapyramidal signs.
Distinguishing pantothenate kinase-associated neurodegeneration from neuronal ceroid-lipofuscinosis may be difficult. Indeed, it has been suggested that PKAN is a form of neuronal ceroid-lipofuscinosis (83). On occasion, it has been observed in patients with acanthocytes in their peripheral blood smear, who had features of neuronal ceroid-lipofuscinosis, including the MRI findings. These patients presented with difficulties before 10 years of age and have had a fulminating course consisting of a mixture of rapidly progressive dystonia, rigidity, and spasticity. No beta-lipoprotein abnormalities were present. Several patients have been reported in the past with acanthocytosis and manifestations of PKAN (61; 84; 44; 39). A patient with acanthocytosis, hypoprebetalipoproteinemia, orofacial dyskinesia, and MRI findings similar to those found in PKAN has been reported. The phenotype was alluded to as hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) syndrome (33). Two other unrelated patients characterized by prominent faciobuccolingual dyskinesia, acanthocytosis, and retinitis pigmentosa have also been reported. Brain MRI demonstrated the "tiger's eye" image of the globus pallidus. The phenotype of these patients closely resembled HARP syndrome, but extensive serum lipid study failed to demonstrate lipoprotein abnormality. As predicted in the past (48), HARP syndrome was found to be allelic to PKAN (07). Therefore, these patients clearly differ from those with the acanthocytosis-choreoathetosis syndrome.
Confusion of PKAN with juvenile Huntington disease, particularly the rigid form, is possible. The autosomal dominant mode of inheritance, usual presence of detectable caudate atrophy, lack of clinical or laboratory retinal or optic nerve changes, as well as lack of peripheral white cell inclusions should distinguish Huntington disease from Hallervorden-Spatz syndrome. It is noteworthy that when chorea is present in juvenile Huntington patients, it usually differs from the choreoathetosis of Hallervorden-Spatz syndrome.
Machado-Joseph disease is inherited as an autosomal dominant trait. It usually begins after age 20 years and manifests with signs and symptoms of spinocerebellar degeneration. A small number of childhood patients have been documented who may have some associated rigidity. Both the manner of inheritance and the ataxia should separate this condition from Hallervorden-Spatz syndrome.
The rare juvenile forms of G(M1) and G(M2)-gangliosidoses may manifest with some changes similar to PKAN, but are usually separable on clinical grounds and can be readily differentiated with laboratory studies.
Genetic studies to determine deficiency of the PANK2 gene are necessary. Conventional laboratory evaluation is unrevealing. The employment of special techniques document increased uptake of iron by the basal ganglia (85; 91; 82; 101; 83). Cultured skin fibroblasts have been reported to accumulate Fe(59)-transferrin (101), although further reports have not appeared and the isotope is no longer available for human use.
Vacuolated circulating lymphocytes, when examined by electron microscopy, contain abnormal cytosomes, including fingerprint, granular, and multilaminated bodies (83; 103). The characteristics of the observed materials suggest the presence of ceroid-lipofuscin, a substance that accumulates in the neuronal ceroid-lipofuscinoses (83). The underlying mechanism of ceroid-lipofuscin storage is unknown, although the possibility of pathologic peroxidation of cell membranes, due to the participation of Fe(2+) in the Fenton reaction, has been hypothesized (57; 81).
Studies of brainstem auditory evoked potentials are usually normal; however, abnormalities of visual evoked responses and electroretinograms are frequently demonstrated. CT studies have been of some value in the study of Hallervorden-Spatz syndrome (93; 05; 88) but have not proved as useful as MRI studies. MRI studies have often, but not uniformly, demonstrated hypointensity in the basal ganglia, most pronounced in the globus pallidus, which is suggestive of storage of an unusual material, probably iron (17; 86; 54; 75). Hallervorden-Spatz syndrome patients often manifest an area of higher signal intensity in the central or anteromedial part of the globus pallidus (63; 75; 02), which has been termed the "eye of the tiger" (75). In the globus pallidus, the area of hypointensity appears to correspond with pallidal necrosis and accumulation of iron deposits, whereas the area of high signal intensity suggests loose tissue with vacuolization and lesser amounts of iron and gliosis (67; 66).
Increased T2 signal intensity in the globus pallidus may resemble the "eye of the tiger" sign in other conditions such as organic acidurias (92; 66), Leigh disease, post-infarction and post-infectious dystonia (63) that could cause neuronal loss, gliosis, and focal axonal swelling (02).
Scans should be performed on equipment utilizing fields of 1.5 Tesla or greater. The normally present high concentration of iron in the basal ganglia in teenagers and adults may confound the interpretation. Scans performed in younger children are more likely to demonstrate a central hypointensity in the globus pallidus (29).
There is no specific treatment for pantothenate kinase-associated neurodegeneration. Potential rational therapies may be aimed at addressing oxidative stress, iron overload, and low levels of CoA in mitochondria (27). Since the identification of the PANK2 deficiency in many patients with PKAN, therapy with vitamin B5 has been attempted. Evidence of efficacy is not available. Thus far, only palliative therapies exist. Stereotactic pallidotomy has been described in a 10-year-old boy with subsequent functional improvement in the use of the limbs and relief from painful dystonia (35). Metaanalysis of globus pallidus pars interna deep brain stimulation in PANK2 patients showed 35% improvement in the Burke-Fahn-Marsden Dystonia Rating Scale Motor Score (BFMMS) and 53% improvement in Burke-Fahn-Marsden Disability Score (BFMDS) (03).
Attempts to remove the excess iron deposits from the brain by the use of systemic iron chelation utilizing desferrioxamine have neither appeared to decrease brain iron stores nor to affect the clinical course. Zorzi and colleagues investigated the chelator deferiprone in 9 patients with pantothenate kinase-associated neurodegeneration with reduction of globus pallidus iron content on MRI imaging but without improvement on Burke‐Fahn and Marsden Dystonia Rating Scales (102). Cossu and associates showed disease stabilization from a motor perspective in 5 out of 6 neurodegeneration with brain iron accumulation patients in a 4-year open-label study of deferiprone (13). Klopstock and colleagues presented a randomized double blind placebo controlled study of deferiprone (37). There was no improvement on the Patient Global Impression of change, but the Barry-Albright Dystonia scale did improve at 18 months of deferiprone treatment. Given the rarity of the disease, treatment data are limited.
Other aspects of management directed at specific symptoms often prove helpful. Dystonia is among the most common associated movement abnormalities. Therapy with levodopa or carbidopa is often effective. When this treatment is ineffective or suboptimal, bromocriptine, either as a separate treatment or in combination with levodopa or carbidopa, is often beneficial. Trihexyphenidyl may be administered if dopaminergic therapy is ineffectual, but appears to be less effective than in other forms of dystonia.
Five patients with generalized dystonia who were refractory to oral medications were treated by continuous intrathecal baclofen infusion. Two of the patients had neurodegeneration with brain iron accumulation. Responsiveness to intrathecally administered baclofen was evaluated after bolus injections in 1 patient, and during continuous infusions via an external micropump in 4. Patients who responded to trial injections were subsequently implanted with a programmable pump for continuous infusion of baclofen. Dystonia related to "cerebral palsy" was substantially improved by continuous intrathecal baclofen infusion in doses of 500 µg/day to 800 µg/day. Benefit has persisted for over 19 months of continuous infusion. Dystonia in the 2 patients with neurodegeneration with brain iron accumulation was not improved, although the screening trial was limited by side effects in 1 patient, and by meningitis in the other (01). Nevertheless, continuous intrathecal baclofen infusion may yet prove beneficial for some patients with neurodegeneration with brain iron accumulation; however, the limited study of these patients is not encouraging. Further trials may resolve the problem of efficacy of this form of therapy in this syndrome.
Unfortunately, pharmacotherapies of dystonia, although sometimes efficacious, also have the potential to be transient. Physical therapy for dystonia is rarely of benefit.
There are no specific therapies for tremor. The tremor is much like that present in Parkinson disease and does not respond to beta-adrenergic blockers. Dopaminergic drugs are often the most efficacious. The use of phenothiazines or butyrophenones is generally contraindicated. Benztropine may be of value in the treatment of both tremor and rigidity. Use of the drug in children should be accompanied by close monitoring for side effects.
Choreoathetotic movements are often present. Therapy with diazepam may be of value. As is the case with seizures, aggravation of dystonia by phenothiazines or butyrophenones usually eliminates these drugs from therapeutic consideration.
The differentiation between rigidity and spasticity may be difficult in some patients with neurodegeneration with brain iron accumulation. Therapy similar to that used in the treatment of dystonia is usually of benefit, including levodopa or carbidopa, bromocriptine, and trihexyphenidyl.
The presence of spasticity is common in Hallervorden-Spatz syndrome. Treatment of spasticity is not unlike that employed in other conditions. The use of muscle relaxants is often beneficial. Baclofen in moderate to large doses, will often relieve the overt stiffness, as well as occasional episodes of muscle spasms. At times, dystonic posturing may also be decreased with the use of baclofen. Dantrolene sodium, although not as effective for most patients, will occasionally be of significant aid. The physician must be cognizant of the adverse reactions that sometimes accompany the use of these drugs. Stretching routines, both passive and active, are often of value when practiced regularly and prudently. As already noted, 2 patients with generalized dystonia secondary to neurodegeneration with brain iron accumulation refractory to oral medications were treated by continuous intrathecal baclofen infusion. Dystonia in the 2 patients was not improved (01).
As a result of disturbance of supranuclear corticospinal tract function, drooling may become a difficult problem. Small doses of atropine or methscopolamine may be useful. If drooling cannot be controlled in a patient who has a relatively prolonged clinical course, surgical management may be indicated (56).
Communication problems caused by dysarthria may dominate the clinical problems for long periods of time. Although dysarthria may improve with drug therapy of dystonia or spasticity, the use of alphabet or word boards or computer-driven voice synthesizers may prove of great help. Speech therapy may improve speech quality during the early stages of dysarthria (76).
Seizure activity requires the administration of antiepileptic drugs. Partial seizures, which is the most common type associated with neurodegeneration with brain iron accumulation, may require antiepileptic drugs. Sometimes the seizures become generalized. Seizures are generally not a major component of the disease. Decreased visual acuity that accompanies optic atrophy is unresponsive to therapy. Conventional, nonspecific approaches to management of visual impairment are usually of no help. No therapy for intellectual deterioration is of value.
If the disease progresses to the point that the patient cannot swallow and nutrition is impaired, gastrostomy placement may prove necessary.
The NBIA Disorders Association of El Cajon, California, is a non-profit organization dedicated to providing emotional support to families, promoting public education, and providing support for research into these disorders. Until 2004 this group was known as the Hallervorden-Spatz Syndrome Association. The website is www.NBIAdisorders.org and the telephone is (619) 588-2315.
Research on future treatments is proceeding. RE-024 (fosmetpantotenate) is designed to overcome the bottleneck in acetyl coenzyme A synthesis caused by PANK2 mutation in PKAN, as it is the product of the pantothenate kinase enzyme. An open-label case report of 2 patients by Roa and colleagues showed improvement on the Movement Disorder Society Unified Parkinson’s Disease Scale, parts 2 and 3, as well as Barry-Albright Dystonia Scale (60). Another open-label case report by Christou and associates noted improvement on the UPDRS, BAD, and EQ-5D-3L scales in a single patient (10). A phase 3 trial is underway (NCT03041116).
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia, Acorda, Adamas, Amneal/Impax, Kyowa Kirin, Lundbeck, Neurocrine, and Teva.See Profile
AHM M Huq MD PhD
Dr. Huq of Wayne State University has no relevant financial relationships to disclose.See Profile
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