Myoclonus epilepsy with ragged-red fibers
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This article includes discussion of Niemann-Pick disease types A and B, acid sphingomyelinase-deficient Niemann-Pick disease, acid sphingomyelinase deficiency, sphingomyelin lipidosis, type A Niemann-Pick disease, type B Niemann-Pick disease, and intermediate type of ASM-deficient Niemann-Pick disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The term “acid sphingomyelinase-deficient Niemann-Pick disease” (“ASM-deficient NPD”) or ASM deficiency (ASMD) is now preferred to collectively designate Niemann-Pick disease types A and B. ASM-deficient NPD is a rare autosomal recessive lysosomal lipid storage disease resulting from mutations in the acid sphingomyelinase SMPD1 gene. This name allows inclusion of cases intermediate between the historical severe neuronopathic type A and the non-neuronopathic type B and clearly differentiates this group from Niemann-Pick disease type C, a distinct entity. In this article, the author updates clinical knowledge from surveys in large cohorts of patients, methods for laboratory diagnosis, and genotype/phenotype correlations. She also discusses the progress towards enzyme replacement therapy in type B patients and other experimental therapeutic approaches.
• Niemann-Pick disease type A and type B are rare autosomal recessive lysosomal lipid storage diseases corresponding to the acid sphingomyelinase-deficient forms of Niemann-Pick disease.
• Classical type A is a severe neurovisceral form with very poor prognosis and limited survival; genetic prevention is crucial.
• The more frequent type B (corresponding to the non-neuronopathic, chronic form with only visceral – mainly spleen, liver, lung – involvement) may be diagnosed from infancy to late adulthood.
• Intermediate forms with mild or late onset neurologic involvement exist.
• For type B patients, enzyme replacement therapy by recombinant acid sphingomyelinase is not yet available, but a phase 2/3 clinical trial is well underway in children and adults.
Niemann-Pick diseases are a heterogeneous group of genetic disorders that share the general clinical and biochemical features of hepatosplenomegaly, with varying degrees of sphingomyelin and cholesterol accumulation in tissues. Their recognition had its genesis in Niemann's report of an 18-month-old girl who had died of a neurodegenerative disorder accompanied by massive hepatosplenomegaly that was followed by the pathological studies of Ludwig Pick (56; 64). Klenk later demonstrated that the predominant stored lipid was sphingomyelin.
In 1958 Crocker and Farber published a review of 18 cases showing that there was a wide variability in age of onset and clinical expression as well as in the level of sphingomyelin storage in tissues (12). This led Crocker to propose a classification of Niemann-Pick disease into 4 subgroups, A to D (11). Type A (corresponding to the original case of A. Niemann) was characterized by severe, early CNS deterioration and massive visceral and cerebral sphingomyelin storage. Type B showed a chronic course with marked visceral involvement, but with a sparing of the nervous system. Types C and D were characterized by a subacute nervous system involvement with a moderate and slower course as well as milder visceral storage. The rare patients with a non-neurologic adult form, later categorized as the E and F subtypes of Niemann-Pick disease, were ill-defined and most likely corresponded to atypical cases with either type C (E) or type B (F). In 1966 Brady and associates demonstrated a severe deficiency in acid (lysosomal) sphingomyelinase activity in tissues from patients with type A (04), a finding that was soon extended to type B, but not to types C and D.
The next step was the identification of the gene encoding acid sphingomyelinase, SMPD1, and the demonstration of mutations in patients (77; 76), confirming that Niemann-Pick disease types A and B were allelic disorders. Meanwhile, type C was shown to constitute a distinct entity, with alterations in trafficking of endocytosed cholesterol and mutations in the NPC1 or NPC2 genes, type D being an allelic NPC1 form (60; 92). An increasing number of patients intermediate between the A and B forms have been described (61; 101; 46), indicating that the clinical spectrum of sphingomyelinase deficiencies forms a continuum, much like the situation in Gaucher disease. Thus, the nomenclature needed to be amended. One should remember that the generic name "Niemann-Pick disease", without specification of a subgroup, is ambiguous because type A and B on 1 side and type C on the other side refer to 2 very distinct disorders. Considering that Niemann-Pick type C is now established under that name, it has been proposed to use for primary sphingomyelinoses (ie, types A, B, and intermediate forms) the collective term of “acid sphingomyelinase-deficient Niemann-Pick disease” (ASM-deficient NPD) or “ASM deficiency” (73).
All types of acid sphingomyelinase-deficient Niemann-Pick disease share involvement of the reticuloendothelial system and are distinguished by the presence (type A and intermediate) or absence (type B) of involvement of the nervous system.
Niemann-Pick disease type A. Most patients show a clinical course similar to that described by Niemann (56), with variations in the intensity of the visceral signs and in the age of onset of neurologic dysfunction. The neonatal period is often normal, with vomiting, diarrhea, or both as first symptoms, most commonly appearing in the first months of life. Failure to thrive often motivates a first consultation leading to the discovery of hepatosplenomegaly, which is a constant sign. Prominent and progressive hepatosplenomegaly and lymphadenopathy occurs in most cases before 3 to 4 months of age, and sometimes earlier. Hypotrophy is observed in 70% of cases. The facial appearance may be unremarkable or may show minor dysmorphy. A brownish pigmentation of the skin may be present. There is no clinical or x-ray evidence of bone abnormalities. Bone marrow contains foamy storage cells. Neurologic onset does not usually occur until 5 to 10 months of age. The first evidence of psychomotor regression may be overlooked due to the severity of visceral signs and poor general condition. The child generally shows hypotonia, progressive loss of acquired motor skills, loss of interest in the surroundings, and reduction in spontaneous movements. At examination, initial axial hypotonia is later combined with bilateral pyramidal signs. Slowed nerve conduction velocity is generally present. The cerebrospinal fluid is normal. Developmental age usually does not progress beyond 9 months for gross motor skills, and acquired skills are lost with progression. The disease progresses with a variable span of evolution towards spasticity and cerebral deterioration (and cachexia without proper nursing). Neurogenic impairment of swallowing is a common feature. Blindness is also frequent. Macular cherry-red spots are a typical feature but may not be present until an advanced stage of the neurologic disease. As the disease progresses, there is increasing tendency to rigidity. Seizures may occur in the later stages of the disease, but are not a major sign. Recurrent respiratory infections are a common complication. Death classically occurs between 1.5 and 3 years of age (76; 45; 78; 46). Cases with a milder systemic involvement, slightly protracted onset of neurologic symptoms, and slower course are also seen.
Niemann-Pick disease type B. Niemann-Pick disease type B is a chronic disease. True type B patients do not have neurologic involvement and are intellectually intact, although ophthalmoscopic examination may reveal retinal macular halo or cherry red maculae (49). The age of discovery is typically in late infancy or childhood but may occur from birth until late adulthood, with about 30% of the patients diagnosed in adulthood. Few longitudinal studies on large cohorts are available, but existing data indicate that a majority of patients survive into late adulthood (94; 49; 29; 39; 40). Some children, however, may have a very severe systemic disease, eventually leading to premature death (35; 103; 61; 07). A few adults may die from liver or heart failure (87; 48; 38; 07; 39), or respiratory failure (48; 07; 39). Studies on morbidity and mortality in type B patients or burden of illness in acid sphingomyelinase deficiency (ASMD) have been published (48; 07; 10). A comprehensive histopathologic study of liver and skin in 17 patients enrolled in the phase 1 therapeutic trial also gave a good overview on the range of alterations (88). Psychosocial aspects of the disease have been discussed (28). The presenting sign in a large majority (close to 80%) of patients is splenomegaly or hepatosplenomegaly (97; 49; 46; 47). Splenomegaly is in general less pronounced than in Gaucher disease; thus, mechanical complications are less severe. Hypersplenism may occur in a small proportion of patients, but splenectomy is seldom necessary (and should be avoided). Bleeding episodes most often involve recurrent epistaxis. In cases presenting in infancy or childhood, retarded body growth, particularly in regard to height, is a common finding between the ages of 6 and 16 years (97; 108; 49). Skeletal age and puberty are often delayed. A later catch-up of growth usually takes place. Apart from liver or spleen enlargement, or both, the most constant associated sign is the presence of radiographic abnormalities of the lung (diffuse, reticulonodular infiltrations), observed in a large majority of patients, associated to a widely variable impairment of respiratory function (52; 82). Pulmonary involvement is common in affected individuals of all ages and can also be severe in children (52; 25; 99; 06). In adults, this may be the presenting sign (49; 39), usually leading to the discovery of a yet unnoticed enlarged spleen. The functional tolerance is often better than the radiologic findings would suggest, but a variable degree of decreased pulmonary diffusion due to alveolar infiltration is very common (52). In adult patients with a long follow-up, pulmonary involvement was in general the main source of complaint, ranging from dyspnea on exertion (frequent) to oxygen dependency in a few patients. Alterations of liver function are in general mild, but possibly underestimated (88); a few patients have been described in whom liver cirrhosis and intrahepatic block developed and led to fatal liver failure (35; 38). Hyperlipemia with low HDL-cholesterol, elevation of LDL-cholesterol and of triglycerides is common, even in children (49). Early coronary disease has been identified in some adults. Other features associated with the disease are joint/limb pain, bruising, headaches, abdominal pain, or diarrhea (49). Severe bone involvement is not a typical complication, but a majority of patients have a decreased bone mineral density, and some have a history of pathological fracture (98; 49; 106).
Intermediate forms. As discussed in the history and nomenclature section, there is a continuum between type A and type B. The small number of sphingomyelinase-deficient patients classified as "intermediate" or "subacute" constitute a heterogeneous category. They include patients closer to type A with a late infantile, juvenile or even adult neurologic onset and a slowly progressive disease (44; 84; 26; 61; 101). A number of such patients originate from Germany and Central Europe. The neurologic findings can include cerebellar ataxia, extrapyramidal involvement, or psychiatric disorders. Some other patients have a clinical course closer to type B than to type A, with minimal nervous system involvement (often peripheral neuropathy) or mild mental retardation (103; 101). A significant proportion of intermediate "variant NP-B" patients have an early death (48). A variable phenotype, with or without neurologic involvement, has been found in patients originating from the Balkan region homozygous for the SMPD1 mutation W391G (p.W393G) (85; 54).
Typical Niemann-Pick disease type A. Prognosis is severe, as the disease invariably leads to death, in classical cases before of 3 years of age, and sometimes later. Swallowing problems, cachexia, and recurrent pulmonary infections are the most common complications. Survival is currently often slightly prolonged with improved management of patients.
Intermediate cases. These patients may show a wide range of variation regarding the age of onset and progression of the neurologic disease and have often a less pronounced systemic involvement.
Niemann-Pick disease type B. There is a wide range of severity within the systemic manifestations (46). Overall, prognosis is generally good, and as more adult patients are known, it seems that a majority of patients have an essentially normal lifespan, although with a variable quality of life. A few patients, however, have been reported to develop severe liver cirrhosis in childhood (35) or in adulthood (87; 48; 38). The most common complication is respiratory insufficiency, which can be already severe in young children (52). A various degree of dyspnea on exertion is a common complaint in adult patients, but a number of patients may become oxygen-dependent. Several cases with severe pulmonary impairment have been documented (06; 57). Height may be below the 3rd percentile in children aged 6 to 12 years. Bone fractures have been reported (98) but are infrequent and seldom invalidating. Bone mineral density, however, is commonly decreased, and most adults are osteopenic or osteoporotic at 1 or more sites (106). Hepatosplenomegaly is often prominent in children but may become less conspicuous in later life. Splenectomy may aggravate the lung disease and lead to other morbidities. Moderate thrombocytopenia is relatively common, together with frequent bruising and nose bleeding. Only 1 study on morbidity and mortality in a large cohort of type B patients has so far been published (48).
Data in a large Ashkenazi Jewish population suggest that the L302P mutation (frequent in this population, see below) appears as a risk factor for Parkinson disease (21). A smaller similar study has been conducted in Chinese (19; 43). Thus far, no such study has been conducted in populations where R608del is the most frequent mutation.
Niemann-Pick disease type A. A male, born following an uneventful pregnancy, was noted to have failure to thrive, frequent vomiting, and rapidly increasing hepatosplenomegaly from the third month of life. The diagnosis was established at 4 months of age by demonstration of sphingomyelinase deficiency. At 6 months of age, hypotonia and slow motor development were apparent. The neurologic evaluation at 8 months of age showed marked delay in development. The child did not sit up, controlled his trunk poorly, had no parachute response, did not reach for objects, and showed no interest for persons or toys. Diffuse hypotonia was present but with apparently preserved muscular strength. Deep tendon reflexes were diminished or absent, which is associated with low nerve conduction velocities. Eye fundus was normal. At the age of 10 months, his weight was 5.5 kg, and he could not sit up. At 19 months, cachexia (5.1 kg, 69 cm), loss of head control, and frank pyramidal bilateral signs with severe spasticity were observed. Swallowing problems began at the age of 23 months, ascites at 26 months, and death occurred at 27 months.
Niemann-Pick disease type B. At the age of 4 years, severe hepatomegaly and moderate splenomegaly were discovered in a male with an uneventful infancy. However, he had normal neurologic and psychomotor development. Chest x-ray showed bilateral reticulonodular infiltrations. Diagnosis was made on a liver biopsy (in 1967, before enzyme assay was available). At 12 years of age, clinical examination was unchanged, except for height at -3.5 standard deviation and weight at -3.1 standard deviation. Pulmonary function was normal despite severe infiltration. Serum cholesterol was elevated at 490 mg/dl. He had delayed puberty and a further decline in height growth between 14 to 16 years of age, with a slow catch up from the age of 16 years (adult height: 1.63 m). At the age of 18 years, pulmonary function showed restrictive syndrome with reduced diffusion and hypoxia on exertion. Currently 45 years of age and without the development of more severe symptoms, he has a normal life and only complains of dyspnea on exertion.
Primary deficiency of the lysosomal acid sphingomyelinase [E.C. 220.127.116.11] resulting from mutations on the SMPD1 gene is the underlying cause. Correlations between certain mutations and a neuronopathic or non-neuronopathic phenotype have been made.
Biochemistry and enzymatic findings. The primary deficiency in lysosomal sphingomyelinase resulting from mutations on the SMPD1 gene leads to the progressive accumulation of sphingomyelin in systemic organs in all types of the disease and in the brain in neuronopathic forms (97; 76). More specially, there is a massive (up to 50-fold) accumulation of sphingomyelin in organs of the reticuloendothelial system, including the liver and spleen, with a lesser and secondary increase of unesterified cholesterol and other phospholipids, including bis(monoacylglycero)phosphate (90; 84). Cerebral storage of sphingomyelin is present in type A only. The brain tissue of type A patients also shows pronounced alterations of the ganglioside profiles, with accumulation of the minor GM2 and GM3 gangliosides (84; 68).
Although a wealth of data are available regarding pathology and neuropathology in patients (17), not much is understood regarding the pathophysiology of the brain dysfunction. Most studies have been conducted in a sphingomyelinase knock out (ASMKO) transgenic mouse model (30; 41; 36; 20). Neuronal death is a prominent feature of the disease, and a patterned death of Purkinje cells has been described (72). Calcium homeostasis was further shown to be altered, with reduced rates of calcium uptake via SERCA (24). Sphingomyelin-induced inhibition of plasma membrane calcium ATPase could be involved in neurodegeneration (62). Increased levels of a potentially apoptotic metabolite, the lysoderivative of sphingomyelin, sphingosylphosphorylcholine (08), have been reported in the brain of type A (but not B) patients as well as in that of ASMKO mice (68). Sphingosylphosphorylcholine (or lysosphingomyelin) is greatly elevated in the liver and spleen of both types (A and B), and a significant increase has been documented in dry blood spots of type B patients (09) and in plasma of type A and B patients (34; 63; 65; 13).
Although the degree of sphingomyelin accumulation is variable in different organs and between type A or B patients, acid sphingomyelinase activity measured in vitro is uniformly defective in all tissues (76). In situ hydrolysis of labeled sphingomyelin by living cultured fibroblasts, however, demonstrates a significant level of residual activity in typical type B patients, suggesting that the mutated enzyme has retained enough catalytic activity to limit accumulation and protect the brain (96; 61). Interestingly, besides its essential function within the lysosomes, a secreted form of acid sphingomyelinase has also been shown to exert an important and complex role at the cell surface, including reorganization of ceramide-rich microdomain structures and activation of apoptotic signaling (83; 75).
Genetics. The disease has an autosomic recessive inheritance. The SMPD1 acid sphingomyelinase gene (GenBank NC_000011.10) is localized on chromosome 11p15.1 to 11p15.4 and consists of 6 exons. Relatively small (approximately 6 kb), it encodes a polypeptide of 631 amino acids with a 48 amino acid signal peptide. The 2 in frame ATG initiation sites are functional in vivo; for more details, see (110). It is located within an imprinted region of the human genome and has been shown to be preferentially expressed from the maternal chromosome (paternal imprinting) (81). By mid 2018, about 250 disease-causing mutations had been reported. For a list of mutations as well as corresponding references, see work by Zampieri and colleagues (110). Note that in order to comply with the guidelines for mutation nomenclature from the Human Genome Variation Society (HGVS), mutations located downstream of nucleotide 142 (codon 48) will now appear with a codon number = p.(n+2), due to a different cDNA reference sequence. The new nomenclature has been kept in this article, with the “historical” one in parentheses. Collectively, 3 mutations, p.R498L (R496L), p.L304P (L302P), and p.P333SfsX52 (P330fs), account for more than 90% of alleles in Ashkenazi Jewish patients with classic type A. A number of other type A-related mutations have been described. In type B patients, p.R610del (R608del) is globally the most common type B mutation (37; 93; 94; 80; 49; 69; 29). It has so far always been correlated with a type B phenotype, even in the heteroallelic status, indicating that 1 copy of this mutation is “neuroprotective” (similar to the N270S GBA1 mutation in Gaucher disease). Highly prevalent in North African type B patients (greater than 90% of alleles) (93), it is also very frequent in Spain (61% of alleles) (69), France (55%) (Vanier personal data; 39), and the Netherlands (52%) (29). It has generally been considered as a “mild” mutation. Among other type B mutations, p.R476W (R474W) and p.L139P (L137P) seem associated with a less severe form, but p.H144Y (H142Y) and p.K578N (K576N, which is frequent in Saudi Arabia) are associated with a severe form. p.A359D, associated with a moderate to severe type B phenotype, is highly prevalent in Chile (01). p.Q294K (Q292K), initially described in patients from Central Europe, is clearly associated with late-onset neurologic involvement (61). p.W393G (W391G), with a demonstrated Rumanian Gipsy origin, is relatively common in patients originating from the Balkanic region. The mutated p.W393G protein and resulting phenotypes have been well studied in a clinical variation described within patients homozygous for this mutation; a majority had systemic symptoms only, but some developed a late-onset neurologic disease (18; 54). In India, a large study revealed a significant prevalence of p.R742* (R740*) (66). The SMPD1 mutation spectrum has also been studied in a fairly large cohort of Chinese acid sphingomyelinase deficiency patients (111).
Mice expressing the p.R498L (R496L) and p.R610del (R608del) mutations on the complete ASM knock-out background have been generated (32).
The disease is pan-ethnic but occurs more frequently in certain populations. Among individuals of Ashkenazi Jewish descent, the combined carrier frequency for the 3 SMPD1 mutations causing the severe neurodegenerative form (type A) has been reported to be between 1:80 and 1:100. Type A seems very rare in other populations; its incidence has been estimated to approximately 1:600,000 living births in France (author’s personal data).
The prevalence of type B is higher in most countries--but largely unknown and most likely under evaluated, as patients with mild manifestations may not be diagnosed. The incidence of type B in France has been estimated to approximately 1:230,000 living births (author’s personal data). The disease seems more frequent in North Africa, especially Tunisia (93; 97; 73; 74), Saudi Arabia (1:40,000 to 1:100,000) (27), and Turkey (80). A founder effect has been described for the p.A359D mutation that is frequent in Chile (1 out of 105.9) (01).
More cases with an intermediate, mild neuronopathic phenotype seem to originate from Central Europe.
Sphingomyelinase deficiencies are genetically inherited following an autosomal recessive mode. Appropriate genetic counseling should be provided to individuals at risk. Prenatal diagnosis is possible either by gene analysis provided that the mutations have been identified in the index case and confirmed by a parental study (91), or by measurement of sphingomyelinase activity. Both DNA and enzyme testing can be done on uncultured chorionic villus sampling, allowing a result at the 11th to 13th week of pregnancy. The tests can also be performed on cultured chorionic villus or amniotic cells, with a result significantly later in pregnancy. For this disease, 1 report of preimplantation diagnosis has been published, but this currently remains an exceptional procedure (27).
Heterozygote detection needs to be done by genetic testing, as enzymatic methods do not clearly discriminate carriers from healthy homozygotes. In the Ashkenazi population, preventive carrier screening and prenatal diagnosis have resulted in a low birth incidence of new patients.
Niemann-Pick disease type A. Other conditions with hepatosplenomegaly and failure to thrive or psychomotor regression must be considered. Among the lipidoses, differential diagnoses of Wolman disease (acid lipase deficiency), Gaucher disease (distinguished by the presence of hypotonia in Niemann-Pick type A and hypertonia in Gaucher), and the neonatal hepatic form of Niemann-Pick disease type C, but also non-dysmorphic forms of GM1 gangliosidosis, need to be considered.
Niemann-Pick disease type B. Various other causes of isolated splenomegaly or hepatosplenomegaly will be excluded by the demonstration of storage cells (foamy macrophages and/or sea-blue histiocytes) in bone marrow; such cells are suggestive of a lysosomal storage disease, but they are not specific of ASMD, nor always present. Differential diagnoses include, among lipidoses, Gaucher disease, Niemann-Pick disease type C (before the onset of neurologic symptoms), cholesterol ester storage disease (acid lipase deficiency), and also glycogen storage diseases.
The diagnosis is established by demonstration of deficient sphingomyelinase activity in leukocytes (or lymphocytes) or in cultured skin fibroblasts (much higher level of activity) (47). The choice of a specific substrate is critical, and patients can be missed by studies on leukocytes using artificial substrates (98; 26). Sphingomyelin radioactively labeled on the choline moiety (natural substrate) should still be considered the gold standard (95; 109), but its use has almost disappeared. Very sensitive methods using a short-chain fatty acid sphingomyelin analogue and detection by ESI-tandem mass spectrometry have a good specificity and are currently recommended (47). They also allow enzyme determination on dried blood spots (Gelb et al 2006; 112; 58) and are used for neonatal screening (51; 05; 102). A number of laboratories use the fluorogenic substrate 6-hexadecanoylamino-4MU-phosphorylcholine, but it is less reliable, and specific pitfalls have been described (89). Although type B patients often show some residual activity, the in vitro assay does not reliably distinguish neuronopathic from non-neuronopathic phenotypes. The loading test in living fibroblasts was more informative but is no longer offered by diagnostic laboratories (61). Genotyping may help to predict a phenotype whenever the diagnosis is made in a young child (47). It is above all important for genetic counseling and heterozygote detection in blood relatives. However, molecular genetic testing should not be used for primary diagnosis in place of biochemical testing.
Several plasma biomarkers show abnormalities. Used in combination, they can constitute a good first orientation test before measuring enzyme activity. Plasma chitotriosidase activity is generally moderately elevated (67), but this finding is unspecific. In plasma, both lysosphingomyelin (difference with Niemann-Pick C) and the so-called “lysosphingomyelin-509” (now identified as palmitoyl-phosphocholine-serine, PPCS) are significantly elevated in acid sphingomyelinase deficiency (23; 34; Pettazoni et al 2017; 65; 13; 100; 40; 79). The oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol (initially developed for initial screening of Niemann-Pick C) are also elevated in ASMD, as well as in acid lipase deficiencies and some nonlysosomal diseases (33; 59; 03). The bile acid derivative N-(3β,5α,6β-trihydroxycholan-24-oyl)glycine is also increased in ASMD (31).
In the past, the diagnostic workup included examination of storage cells in bone marrow and even sometimes a liver biopsy. These invasive approaches are no longer needed, especially as the finding of foam cells, sea-blue histiocytes, or both is not specific. Note that sphingomyelin storage can eventually be demonstrated in retrospect by biochemical studies on autopsy or splenectomy samples.
Routine laboratory workup may reveal a thrombocytopenia, slightly abnormal liver function tests with moderate bilirubin elevation, and often, clear abnormalities of the fasting lipid profile (high total cholesterol values with particularly low HDL-cholesterol and hypertriglyceridemia) (49).
Evaluation following initial diagnosis should include an ophthalmologic examination, a comprehensive neurologic evaluation, a chest radiograph, and in old enough patients, pulmonary function testing. Transient elastography (FibroScan) for the assessment of liver fibrosis may also be performed. Laboratory tests should include blood cells count, clotting tests, liver function tests, and lipid profile. Depending on the clinical status, examination of the skeleton, including DEXA scan, could also be considered (106).
To date, management of all types of ASM-deficiency Niemann-Pick disease is still essentially symptomatic. Information and support to families can be obtained through organizations devoted to inherited metabolic diseases or lysosomal storage diseases. Organizations specific to Niemann-Pick diseases exist in several countries (United States, Canada, United Kingdom, Germany, Spain, The Netherlands, Italy, France, Poland, Argentina, Russia, Japan, China…). Genetic counseling should be made available for family members.
Symptomatic management. Management of type A patients includes physiotherapy to prevent contractures, treatment of infections, and appropriate treatment of feeding difficulties (including nasogastric tube-feeding or gastrostomy). Follow-up of type B patients should in particular include regular monitoring for hypersplenism and pulmonary function (including measurement of DLCO), as well as liver function and fasting lipid profile. Thrombocytopenia may lead to bleeding. A few patients may evolve to liver cirrhosis. Note that total splenectomy should be a last resort as it may worsen the interstitial pulmonary disease. Some patients with symptomatic pulmonary disease (including some children) may require various levels of oxygen therapy. Many type B patients have hypercholesterolemia, and adults should be treated with concomitant monitoring of their hepatic function. Pulmonary lavage has been proposed in patients with severe respiratory disease but is controversial (73). It may have a temporary effect, but inflammatory cells are likely to repopulate the airways. Three patients (1 of whom with a previous liver transplant) received a lung transplantation, with limited follow-up in the 2 surviving patients (14; 42; 57).
A consensus guideline of recommended routine clinical assessments necessary for monitoring the multisystemic manifestations across the spectrum of ASMD phenotypes has recently been published; it also includes options for treatment, interventions, an dlifestyle changes (102).
Current status of specific enzyme replacement therapy. Patients with type B Niemann-Pick disease are appropriate candidates for enzyme replacement therapy, an approach that has proven successful in Gaucher type 1 disease and later in several other lysosomal diseases. The proof-of-concept was obtained early, in a preclinical trial where infusion of recombinant human acid sphingomyelinase into ASMKO mice showed correction of the storage process in liver, spleen, and, to a lesser extent, lungs (but, as expected, not in brain). It, however, took more than a decade before a phase 1 monocentric clinical trial with escalating doses was completed in 11 (adult) patients; highest doses were associated with an increase of c-reactive protein, bilirubin, and ceramide, indicating a need for initial "debulking" (50). A phase 1b (within-patient dose escalation) in 5 adult patients has provided further safety data and efficacy data after 30 months treatment (107; 104). A multicentric phase 2/3 trial (NCT02004691) involving adult type B patients as well as a trial involving children/adolescents is well underway.
Bone marrow transplantation has shown no evidence of neurologic improvement in type A or severe intermediate patients (55; 53). Although it significantly improved the lipid storage in 1 type B case, bone marrow transplantation remains a theoretical option in such patients due to the risks and the limitation of matched donors.
Experimental studies towards future therapeutic directions. Methods to improve enzyme replacement therapy (especially lung delivery) by new enzyme targeting approaches are currently investigated in the ASMKO mouse model. One such approach is the use of a cell adhesion molecule ICAM1 for delivery, independently of the mannose-6-phosphate system (73; 22). Repeated intranasal administration of the recombinant enzyme was also tested (113) and shown to reduce sphingomyelin levels in the lung as well as in the liver and spleen.
An extensive number of studies towards neural progenitor injections and gene therapy have also been conducted in the ASMKO mouse (73; 74). AAV-mediated hepatic expression of acid sphingomyelinase had a profound effect on the reticuloendothelial system organs but not on brain (02); however, by intracerebral or, better, intracerebroventricular gene transfer, a remarkable improvement of the cerebral pathology and of the lifespan was observed (15; 16; 114). A first safety study of AAV2-mediated human acid sphingomyelinase (hASM) in the nonhuman primate brain revealed an inflammatory response (70). Encouraging data have, however, been obtained by cerebellomedullary cistern injection of AAV-9hASM (71). A number of experimental data have suggested that low levels of enzyme activity in the brain could have a major impact on the neurologic disease, provided the delivery occurred prior to onset of neurologic symptoms, which is a major limitation (73; 74).
The issue of pregnancy is applicable to Niemann-Pick type B patients. In some patients, the platelet count may drop due to combined hypersplenism and hemodilution and should be monitored especially in the third term of pregnancy. There are also potential mechanical problems due to hepatosplenomegaly, but in the experience of this author and of Dr. McGovern (reported as personal communication in GeneReviews), most pregnancies in Niemann-Pick disease type B women are uneventful. There is only a single report of fatal postpartum hemorrhage in literature (86). In terms of genetic risk, when the father is not a carrier (usual case), there is no risk for the child to be affected, but all children will be obligate carriers.
Marie T Vanier MD PhD
Dr. Vanier, Director of Research Emeritus at Institut National de la Santé et de la Recherche Médicale, received honorariums and travel reimbursement from Actelion and Sucampo as a member of a scientific advisory board, from Shire as a speaker in postgraduate courses, and from Mallinckrodt as a speaker at an advisory board. She also received honorariums from Shire as a member of a data and safety monitoring board.See Profile
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.See Profile
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Childhood Degenerative & Metabolic Disorders
In this article, the authors review the history of the discovery of phenylketonuria, one of the oldest known inborn errors of metabolism, and review
Apr. 01, 2021
Behavioral & Cognitive Disorders
Mar. 31, 2021