Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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Fucosidosis is an autosomal recessive disorder resulting from a deficiency of alpha-L-fucosidase, encoded by the FUCA1 gene. Individual patients may represent a continuum within a wide spectrum of severity. The more severely affected patients present within the first year of life with psychomotor retardation, coarse facies, growth retardation, and dysostosis multiplex. Patients with milder phenotypes develop angiokeratoma and have longer survival. The enzyme defect results in the accumulation and excretion of a variety of glycoproteins, glycolipids, and oligosaccharides containing fucoside moieties. Diagnosis should be suspected on detection of excess oligosaccharides in urine but must be confirmed by demonstrating low alpha-L-fucosidase activity in peripheral white blood cells. MRI and MR spectroscopy are of substantial diagnostic value. Pallidal lesions resembling the eye-of-the-tiger sign suggest iron accumulation.
• Fucosidosis presents with a spectrum of neurologic and skeletal abnormalities.
• Fucosidosis is caused by a deficiency of alpha-L-fucosidase, encoded by the FUCA1 gene.
• Typical MRI features of fucosidosis combine globi pallidi hyperintensity on T1-weighted images that are hypointense on T2-weighted images with diffuse hypomyelination.
• Proton MR spectroscopy may show specific diagnostic abnormalities in patients with fucosidosis.
• Early hematopoietic stem cell transplantation should be considered in patients with the less aggressive form of fucosidosis.
Fucosidosis, a progressive mental retardation syndrome involving lysosomal storage, was first described by Italian pediatrician Paolo Durand and colleagues in 1966 (07; 08). Fucosidosis involves both fuco-oligosaccharide and fuco-glycosphingolipid storage (05). One of the original names for the disease, "mucolipidosis F," was derived from the second patient to be described (30) because the phenotype was reminiscent of patients with mucopolysaccharide storage diseases. Other forms of fucosidosis show angiokeratomas reminiscent of Fabry disease without substantial skeletal abnormalities (56; 16). Numerous phenotypes are unrelated to either the genotype or the resulting level of residual enzyme activity. The FUCA1 gene and a pseudogene, FUCA1P, have been cloned, and numerous mutations have been shown to cause fucosidosis (12; 59; 45; 46; 44; 47; 58).
• Fucosidosis results in progressive neurologic deterioration, skin abnormalities, growth retardation, skeletal disease, and coarsening of facial features.
• There are two major subtypes of fucosidosis: (1) type I, a severe subtype with rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life; and (2) type 2, a milder subtype with milder psychomotor retardation and neurologic signs, development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival.
• Fucosidosis has a wide continuous clinical spectrum, and individuals with the same mutation may have different phenotypes.
Fucosidosis results in progressive neurologic deterioration, skin abnormalities, growth retardation, skeletal disease, and coarsening of facial features. Clinical manifestations (in decreased order of frequency) include progressive mental degeneration (95%), motor degeneration (87%), coarse facial features (79%), growth retardation (78%), recurrent infections (78% of patients), dysostosis multiplex (58%), angiokeratoma (52%), visceromegaly (44%), and seizures (38%) (56). The recurrent infections may include chronic rhinosinusitis (38).
There are two major subtypes of fucosidosis: (1) type 1, a severe subtype with rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life (08); and (2) type 2, a milder subtype with milder psychomotor retardation and neurologic signs, development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (30; 27). A possible third subtype of fucosidosis, either a variant of type 2 or a distinct type 3, is a juvenile form of the disease with less rapid psychomotor and neurologic deterioration, angiokeratoma resembling the rash of Fabry disease, and possible survival into the twenties (43).
Fucosidosis has a wide continuous clinical spectrum, and individuals with the same mutation in the homozygous state may have different phenotypes, with either rapidly or slowly progressive disease (04; 56; 50; 01). Varying phenotypes (types 1 and 2) and disease severity have been observed within the same family. There is intrafamilial variability in severity (eg, with some affected siblings having type 1, and others having type 2, disease), even among homozygous patients (55; 56; 41). Very low to negligible residual fucosidase enzyme activity has been found in patients of both fucosidosis types 1 and 2 (56). Therefore, the distinction between types 1 and 2 of the disease may not reflect true genetic heterogeneity (56).
Atypical cases have been reported (10; 15). A 14-year-old girl was reported with recurrent infections, progressive dystonia, and mental retardation; early childhood onset; and neither dysostosis multiplex nor organomegaly (15). One affected woman with a homozygous leu405-to-arg mutation in the FUCA1 gene and who was born to consanguineous parents lived until at least the fifth decade (she was 46 at the time of the last report) (10). By the age of 20, she had progressive physical and mental retardation, short stature, angiokeratoma corporis diffusum, dysostosis multiplex generalized muscle wasting, hypohidrosis, and poor temperature regulation (39). By the age of 46, she had lost all verbal and most nonverbal communication and was unable to either sit unaided or ambulate. She had suffered continued muscle wasting, several minor long-bone fractures, and one chest infection. Angiokeratomas were prominent on her trunk and legs, but there had been little evident progression of these between the ages of 20 and 46. The authors noted that this is a recognized feature of this disorder.
Prognosis is poor and degeneration is progressive, although the symptoms may be mild enough to permit life beyond adolescence. Most patients reach the second decade of life, with only about 10% dying before the age of 5.
Case 1. A 15-year-old Japanese girl developed normally until 1 year of age (01). She began walking at the age of 19 months, and by 23 months, she had evident speech delay and hearing difficulties. By 3.5 years of age, she had coarse facial features, small stature, and kyphoscoliosis. She did not have organomegaly or mucopolysacchariduria. Alpha-L-fucosidase activity was profoundly impaired (0 nmol/hr/mg protein compared with 29.1 ± 4.7 nmol/hr/mg in controls). By 4 years of age, angiokeratoma appeared on her palms. Bone abnormalities and motor dysfunction gradually progressed, and at 6 years of age, she was unable to walk. Myoclonic seizures subsequently developed, and by 13 years of age, she had evident spasticity and dystonia of all extremities. The angiokeratoma generalized, and puberty did not develop.
Case 2. A 16-year-old Bulgarian girl who was born prematurely at 25 weeks of gestation initially met developmental milestones at age-appropriate intervals (ie, consistent with corrections for gestational age) (23). She had a 15-word vocabulary by 18 months (most children have a 10- to 15-word vocabulary by this time), but she walked a bit late, at 2 years of age (corrected age: 20 months). Language began to regress around 24 months, and she subsequently lost motor milestones. Neurology and genetics evaluations raised suspicion of a glycoprotein storage disorder, and she was ultimately diagnosed with fucosidosis by enzyme analysis around 2.5 years of age. Later genetic testing disclosed a mutation [194G>A (p.Gly65sp)] in exon 1 of the FUCA1 gene. Both parents were carriers of this mutation; her elder sister had no manifestations of this disease.
Cognitive and motor regression continued, compounded by failure to thrive, multiple contractures, and hip dysplasia. Her cognitive function at the age of 5 years was equivalent to that of a child less than 12 months old. She stopped walking and scoliosis was evident at around the age of 7. By the age of 12, she developed recurrent pneumonia and frequently required hospitalization. Epilepsy with generalized tonic-clonic seizures began at the age of 14. She also developed dystonia involving her tongue, face, neck, and right arm and leg. She had coarse gargoyle-like features, macroglossia with a protruding tongue, recalcitrant nasal polyposis, chronic respiratory distress with recurrent respiratory infections, gastroesophageal reflux disease, and angiokeratomas on her lower extremities and trunk. Her skeletal system and extremities became increasingly malformed due to the extensive dysostosis multiplex (ie, chondrodystrophic skeletal changes and diffuse deposition of a lipid-like substance in body tissues), which caused severe scoliosis, multiple contractures, and foreshortened limbs. Although globally impaired and unable to speak, she had some preserved receptive language by the parents’ report.
MRI at 4 years of age showed characteristic, symmetric, curvilinear bands in the globi pallidi on fluid-attenuated inversion recovery (FLAIR) images. The subcortical and deep white matter showed variably severe, symmetrical increases in T2 signal intensity and reduced white matter volume, with corresponding atrophic enlargement of the lateral ventricles. The corpus callosum was thin. MR spectroscopy showed a prominent peak at 3.8 to 3.9 ppm and a doublet peak at 1.2 ppm.
Curvilinear bands in the globi pallidi in a 4-year-old girl with fucosidosis. MRI fluid-attenuated inversion recovery (FLAIR) image of the brain in the horizontal section showing characteristic symmetric curvilinear bands in th...
Atrophic enlargement of the lateral ventricles, with reduced white matter volume and abnormal white matter signal intensity in a 4-year-old girl with fucosidosis. T2-weighted MRI image of the brain in the horizontal section sho...
MRI of the sagittal section showing thinning of the corpus callosum (arrow) in a 4-year-old girl with fucosidosis. (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and supportive management of fucosidos...
Magnetic resonance spectroscopy showing a prominent peak at 3.8 to 3.9 parts per million (white arrow) in a 4-year-old girl with fucosidosis. (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and support...
Magnetic resonance spectroscopy showing a doublet peak around 1.2 parts per million (white arrow) in a 4-year-old girl with fucosidosis. (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and supportive m...
Bone marrow transplantation, hematopoietic stem cell transplantation, and umbilical cord blood transplantation were considered, but the family opted for symptomatic management because of the child's advanced and irreversible disease burden.
There were many specific aspects of her late disease management. Recalcitrant nasal polyposis was managed with bimonthly nasal endoscopy, nasal polyp removal, and daily sinus rinse of saline mixed with gentamicin and budesonide. Lower respiratory tract symptoms were managed with oxygen, albuterol, and fluticasone inhalers; nebulized beclomethasone; oral clindamycin; and an airway clearance system. Seizures were controlled with levetiracetam. Dystonia was treated with baclofen, botulinum toxin injections, and physical, occupational, and massage therapy.
• Fucosidosis is an autosomal recessive lysosomal storage disease caused by a deficiency of lysosomal alpha-L-fucosidase, which is required to metabolize certain complex compounds containing the hexose deoxy sugar fucose.
• Deficiency of acid alpha-L-fucosidase impairs or prevents catabolism of fucose-containing glycoproteins and certain blood group–related glycosphingolipids.
• The inability to break down fucose-containing compounds results in their accumulation in various tissues in the body.
• Although fucosidosis is primarily a polioencephalopathy (ie, disorder of the grey matter), some dysmyelination is also common.
Fucosidosis is an autosomal recessive lysosomal storage disease caused by homozygous or compound heterozygous mutations in the FUCA1 gene (OMIM 612280) on chromosome 1p36 (45; 37; 53; 48; 54; 06; 60). Most of the pathogenic variants in the FUCA1 gene that are related to fucosidosis are missense/nonsense substitutions, with less common deletions or splice site variants (48). Mutations in the FUCA1 gene result in a deficiency of lysosomal alpha-L-fucosidase, which is required to metabolize certain complex compounds containing the deoxyhexose sugar fucose.
L-fucose is a hexose deoxy sugar found on N-linked glycans on the cell surface. The lack of a hydroxyl group on the carbon at the 6-position makes it a deoxy sugar.
Fucosylation is a common post-translational modification: fucose-containing glycans normally participate in ABO blood grouping, antibody effector functions, lymphocyte development and selectin-mediated leukocyte-endothelial adhesion, and numerous ontogenic events (eg, signaling events by the Notch receptor family) (02; 26). Deficiency of acid alpha-L-fucosidase impairs or prevents catabolism of fucose-containing glycoproteins and certain blood group–related glycosphingolipids. The inability to break down fucose-containing compounds results in their accumulation in various tissues in the body. The major storage materials that accumulate in the brain are an oligosaccharide (Fuc-Gal-GlcNAc-Man[Fuc-Gal-GlcNAc-Man]-ManGlcNAc) and a disaccharide [Fuc(a, 14 6)-GlcNAc] in the approximate ratio of 5:1 (51).
There is biochemical heterogeneity in fucosidosis (14; 21). In patients with less than 5% of normal alpha-L-fucosidase activity, some synthesize no detectable enzyme protein and a smaller proportion synthesize normal amounts of the 53,000-Da precursor, but none of the mature 50,000-Da form is detectable (21).
Neuropathological studies show prominent neuronal loss in the thalamus, hypothalamus, cerebral cortex, Purkinje cells, and dentate nucleus. Nerve cell bodies are distended with unusual lamellated fibrogranular intracellular inclusion bodies as a result of glycolipid accumulation. Oligodendrocytes and astrocytes show vacuolation. Although fucosidosis is primarily a polioencephalopathy (ie, disorder of the grey matter), some dysmyelination is also common. However, it is not as severe as that seen in primary leukoencephalopathies (eg, metachromatic leukodystrophy).
Accumulating metabolites appear on electron microscopy in the form of large, clear inclusion bodies containing some lipid-positive multilamellar structures (glycolipid) and nonosmiophilic, finely reticular material (oligosaccharide or mucopolysaccharide). Vacuolated histiocytes and macrophages are common in peripheral blood (08; 30).
Oligodendrocyte loss during myelination contributed to hypomyelination in a canine model (11).
• Fucosidosis is a rare disorder (incidence below 1 in 200,000 live births), with some "clusters" reported in the United States and Italy, but most cases are sporadic.
• Fucosidosis occurs worldwide without an evident ethnic predisposition.
Fucosidosis is a rare disorder (incidence below 1 in 200,000 live births and fewer than 120 cases reported worldwide), with higher incidence rates reported in Italy (localized communities in Calabria), the Hispanic-American population of the United States (Colorado and New Mexico), and Cuba (42; 57; 37; 54). Fucosidosis occurs worldwide (16; 44; 32). Seven different mutations have been identified among nearly 20 patients reported from Italy, with p.P141fs and p.G60D mutations present in more than 50% of the cases.
Prenatal diagnosis is possible, and carrier detection is reliable.
Angiokeratoma and mildly coarse facies in an intellectually disabled child may distinguish fucosidosis from other lysosomal storage diseases, but biochemical tests are essential to distinguish fucosidosis from mannosidosis and aspartylglycosaminuria. Progressive changes on neuroimaging may be helpful in identifying fucosidosis (49).
Plain films. In fucosidosis, skeletal x-rays commonly show delayed skeletal maturation, osteopenia, kyphosis or scoliosis, and dysostosis multiplex. Dysostosis multiplex particularly affects the spine, pelvis, epiphyses of long tubular bones, metacarpals, and skull. Additional plain film findings may include the following: (1) flattening and anterior beaking of the lower thoracic and lumbar vertebrae; (2) widening, scalloping, and sclerosis of the diaphyses of long bones; (3) acetabular widening and flaring of iliac bones; (4) skull thickening; and (5) poorly developed sinuses (31).
Neuroradiology. CT features include hypodensity of the corona radiata, globi pallidi, and internal medullary laminae of the thalami (24; 40; 49). CT is not as sensitive as MRI for detecting significant cranial pathology in fucosidosis.
With brain MRI, T2-weighted and FLAIR images often show diffusely hyperintense signal in the white matter, particularly affecting the periventricular cerebral white matter. Serial imaging shows progressive changes in the signal intensity of the white matter, including the corpus medullare cerebelli; periventricular, lobar, and subcortical supratentorial areas; internal and external capsules; and internal medullary laminae of the thalami (13). The prominent white matter abnormalities observed in fucosidosis have been variably attributed to deficient myelination or severe demyelination, although the extensive, symmetrical, and often confluent white matter signal alteration is more consistent with findings expected in inherited myelin disorders and toxic encephalopathies than in acquired demyelinating disorders (13).
The globi pallidi and substantia nigra may show high-signal intensity on T1-weighted images and low-signal intensity on T2-weighted and FLAIR images (13).
T2-weighted and FLAIR images often show low intensities in the basal ganglia, often without a corresponding CT abnormality (49; 17; 13; 18; 19; 25; 31; 09). Subtle areas of symmetric hyperintensity may be evident in the globi pallidi on T1-weighted images (31). The low intensities of basal ganglia on T2-weighted images seem characteristic and fairly specific for fucosidosis (17).
Although much of the basal ganglia appears hypointense on T2 FLAIR images, curvilinear streaks of abnormal increased signal intensity are often evident within the lentiform nucleus bilaterally. These appear to represent involvement of the medial and lateral medullary laminae—layers of ascending myelinated fibers that separate, respectively, the medial pallidal segment from the lateral pallidal segment and the lateral pallidal segment from the medial aspect of the putamen (13). The combination of hypointensity within the globi pallidi and hyperintensity of their I medullary laminae on T2 FLAIR MR images appears to be specific to fucosidosis (13).
Cerebral and cerebellar atrophy may be evident in patients with fucosidosis, particularly in older patients with fucosidosis type II (17; 13). The combination of increased cerebellar volume in the early stage of fucosidosis with atrophy of the cerebellum during the later course may be pathognomonic of fucosidosis (22).
Laboratory studies. Serum or plasma can be used to show a profound (0% to 15%) deficiency of the ability to hydrolyze 4-methylumbelliferyl-alpha-D-fucopyranoside at pH 5.0 in sodium acetate buffer (08; 36). Leukocytes, cultured fibroblasts, amniotic fluid cells, and tissue biopsy samples have all been used to give an unambiguous diagnosis based on alpha-L-fucosidase deficiency where other lysosomal enzymes are normal or elevated. Patients with fucosidosis are typically deficient in fucosidase enzyme protein, although at least two patients with inactive enzyme protein have been identified (21). Invasive procedures are not required for diagnosis. Detection of storage material [primarily (Fucose)1-(N-acetylglucosamine)1] in urine and tissues has been achieved by various chromatography procedures (36; 51) or mass spectrometry (03). Alpha-L-fucosidase deficiency, along with other lysosomal enzymes, can now be included in newborn screening using tandem mass spectrometry (29).
Sequencing of the FUCA1 gene can be done routinely, and whole exome sequencing can be used to identify mutations (37). The most common FUCA1 mutation is p.Q281R. Interestingly, like some other lysosomal diseases, blood chitotriosidase is moderately elevated in children with fucosidosis, suggesting macrophage involvement (34).
• Treatment is generally symptomatic, but efforts at allogenic bone marrow and stem cell transplantation in humans and animal analogues are encouraging.
Treatment is generally symptomatic, but efforts at allogenic bone marrow and stem cell transplantation in humans and animal analogues are encouraging.
Hematopoietic cell transplant is a potential therapeutic option for the glycoprotein group of lysosomal storage diseases because it introduces functional enzyme-producing cells into the bone marrow and blood, along with engraftment of healthy donor cells into the CNS (presumably as brain macrophages or microglial cells) (35). Due to the rarity of fucosidosis, few transplants for fucosidosis have been performed.
A successful allogenic bone marrow transplant was reported in an 8-month-old boy whose older brother had been diagnosed with fucosidosis (52). The child was asymptomatic, and his development was normal, but there was biochemical evidence of fucosidosis homozygosity and abnormal MRI. In the absence of a suitable related donor, an unrelated volunteer donor was used. Engraftment was documented, including by the presence of donor levels of alpha-fucosidase. The post-transplant course was complicated by moderate graft-versus-host disease. Eighteen months after transplant, there was evidence of mild neurodevelopmental delay, whereas his older brother had far greater developmental delay at the same age. The patient's MRI showed short-term improvement.
The 18-month-old daughter of nonconsanguineous parents was diagnosed with fucosidosis after her older sister was shown to be affected (33). In the absence of a suitable related donor, an unrelated volunteer donor was used; however, at this point, neurologic involvement was clinically detectable. MRI showed diffuse hypomyelination, and auditory and somatosensory evoked potentials were altered. The post-transplant course was complicated by moderate graft-versus-host disease. Polymorphisms on peripheral blood and bone marrow cells documented the persistence of donor engraftment. Follow-up showed a progressive rise of enzyme levels. Psychomotor development, evoked potentials, and MRI all improved.
Umbilical cord blood transplantation is a novel approach for treating patients with fucosidosis who lack suitable bone morrow donors (28; 20). Following cord blood transplantation, a symptomatic 3-year-old patient showed improvement in myelination by MRI and stabilization of developmental abnormalities compared to an untreated child of a similar age who developed brain atrophy and declining neuromotor abilities (20).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.See Profile
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