Behavioral & Cognitive Disorders
Fragile X syndrome
Nov. 21, 2022
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The term "acid sphingomyelinase deficiency (ASMD)“ or "acid sphingomyelinase-deficient Niemann-Pick disease” should now be preferred to collectively designate Niemann-Pick disease types A and B. Acid sphingomyelinase deficiency 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 infantile neuronopathic type A and the non-neuronopathic type B; it also 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 summarizes 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 (ASMD).
• Infantile neurovisceral acid sphingomyelinase deficiency (classical type A) is a severe neurovisceral form associated with very poor prognosis and limited survival.
• The more frequent chronic visceral acid sphingomyelinase deficiency (type B) typically shows only visceral, mainly spleen, liver, lung involvement, and may be diagnosed from infancy to late adulthood.
• Chronic neurovisceral acid sphingomyelinase deficiency refers to intermediate forms with mild or late onset neurologic involvement.
• Status of enzyme replacement therapy by recombinant acid sphingomyelinase: 12-month results of clinical trials have been published for adults and children with chronic visceral acid sphingomyelinase deficiency. Treatment with olipudase alfa of noncentral nervous system manifestations of acid sphingomyelinase deficiency in pediatric and adult patients is now approved in the European Union, Japan, and the United States.
Niemann-Pick diseases constitute 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 Albert Niemann's report of an 18-month-old girl who had died of a neurodegenerative disorder accompanied by massive hepatosplenomegaly, which was followed by the pathological studies of Ludwig Pick (51; 56). Klenk later (1933) demonstrated that the predominant stored lipid in those patients was sphingomyelin. In 1946, Pfändler and Dusendschon described 2 adult brothers with similar pathologic findings, but distinct from Niemann’s patients by a later onset of disease symptoms and the lack of central nervous system (CNS) manifestations. In 1958, Crocker and Farber published a review of 18 cases of “Niemann-Pick disease,” 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 (08). This led Crocker to propose a classification of Niemann-Pick disease into 4 subgroups, A to D (07). Type A (corresponding to the original case of Albert 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 and massive sphingomyelin storage, but with a sparing of the nervous system. Types C and D (the latter corresponding to patients from Nova Scotia) were characterized by a subacute nervous system involvement with a moderate and slower course, as well as milder visceral storage (48). An increasing number of patients intermediate between the A and B forms were also described (53; 84), indicating that the clinical spectrum of acid sphingomyelinase deficiency forms a continuum, much like the situation in Gaucher disease. From 1985 and later, types C and D were defined as a distinct entity, with alterations in trafficking of endocytosed cholesterol and mutations in the NPC1 (including the type D isolate) or the NPC2 gene (see Niemann-Pick disease type C chapter).
The generic name "Niemann-Pick disease” is, thus, ambiguous because it corresponds to 2 distinct disease entities. Furthermore, the historical distinction of 3 types (A, B, C) adds to the confusion. Therefore, the collective term of “acid sphingomyelinase deficiency” (ASMD) has been proposed to specifically designate primary sphingomyelinoses (ie, types A, B, and intermediate forms) (65). In this new nomenclature, which is increasingly used in current literature, infantile neurovisceral acid sphingomyelinase deficiency corresponds to the historical type A, chronic neurovisceral acid sphingomyelinase deficiency to the intermediate forms, and chronic visceral acid sphingomyelinase deficiency to the historical type B.
• All types of acid sphingomyelinase-deficient Niemann-Pick disease share involvement of the reticuloendothelial system.
• They are distinguished by the presence (type A and intermediate) or absence (type B) of involvement of the nervous system.
• The finding of one copy of the SMPD1 p.Arg610del variant in a patient with proven acid sphingomyelinase deficiency is predictive of a chronic visceral form of the disease (type B).
Niemann-Pick disease type A/infantile neurovisceral acid sphingomyelinase deficiency. Most patients show a clinical course similar to that described by Niemann (51), 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 first symptoms of vomiting, diarrhea, or both, 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 occur 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 nutrition and nursing care). 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 are uncommon but may occur in the later stages of the disease. Recurrent respiratory infections are a common complication. Death classically occurs between 1.5 and 3 years of age, most often from respiratory infection and failure (39; 69; 40). Cases with a milder systemic involvement, slightly protracted onset of neurologic symptoms, and slower course, overlapping with the intermediate type, are also seen.
Niemann-Pick disease type B/chronic visceral acid sphingomyelinase deficiency. 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 (44). 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. The presenting sign in a large majority (close to 80%) of patients is splenomegaly or hepatosplenomegaly (44; 40; 41). In general, splenomegaly is 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, which may result from thrombocytopenia due to splenic sequestration, most often involve recurrent epistaxis. In cases presenting in infancy or childhood, stunted body growth, particularly in regard to height, is a common finding between the ages of 6 and 16 years (92; 44). 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), which are observed in a large majority of patients and are associated with a widely variable impairment of respiratory function (46; 73). Pulmonary involvement is common in affected individuals of all ages and can also be severe in children (46; 20; 82; 03; 43). In adults, this may be the presenting sign (44; 34), 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 (46). 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. In general, alterations of liver function are mild (40), but possibly underestimated (76); a few patients have been described in whom liver cirrhosis and intrahepatic block developed and led to fatal liver failure (30; 33). Hyperlipemia with low HDL-cholesterol, elevation of LDL-cholesterol, and of triglycerides is common, even in children (44). Early coronary disease has been identified in some adults (42). Other features associated with the disease are joint/limb pain, bruising, headaches, abdominal pain, or diarrhea (44). 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 (81; 44; 89). The burden of disease—more specially the needs for medical services—was evaluated in a cohort of 81 patients from the United States, Brazil, and Canada (06). Psychosocial aspects and impact of the disease from a patient and caregiver perspective have also been studied (23; 57), showing limited physical activity and negative impact on social function and relationships as important stressors. Data from existing longitudinal studies on large cohorts indicate that a majority of patients survive into late adulthood (44; 24; 34; 35; 43). Some children, however, may have a very severe systemic disease, eventually leading to premature death (30; 86; 53; 04). Causes of morbidity and mortality in type B patients mostly involve respiratory insufficiency and liver disease (42; 04). A histopathologic study of baseline liver biopsies in 17 adult patients screened for the phase 1 enzyme replacement therapy trial with olipudase alfa gave a good overview on the range of liver alterations; a variable degree of fibrosis was observed in nearly all patients, with progression to cirrhosis in 2 patients who did not have any clinical symptoms of liver failure; there was also a wide variability in the degree of sphingomyelin accumulation, which did not correlate with the grade of fibrosis (76).
Intermediate forms/chronic neurovisceral acid sphingomyelinase deficiency. As discussed in the history and nomenclature section, there is a continuum between type A and type B. The small number of acid sphingomyelinase deficiency patients classified as "intermediate" or "subacute" or “type A/B” 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, a number of which originate from Germany and Central Europe (21; 53; 84; 43). Patients homozygous for the SMPD1 p.Q294K variant typically present an intermediate form. 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 (86; 84). A significant proportion of intermediate "variant NPB" patients have an early death (42).
Typical Niemann-Pick disease type A/infantile neurovisceral acid sphingomyelinase deficiency. 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 (maintenance of nutritional status, control of fluid retention, supplemental oxygen and/or noninvasive positive pressure ventilation, spasticity management). Early palliative care is recommended (85).
Intermediate cases/chronic neurovisceral acid sphingomyelinase deficiency. 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/chronic visceral acid sphingomyelinase deficiency. There is a wide range of severity within the systemic manifestations (40; 43). 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 (30) or in adulthood (42; 33). The most common complication is respiratory insufficiency, which can be already severe in young children (46). A varying 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 (03; 52). Height may be below the third percentile in children aged 6 to 12 years. Bone fractures have been reported but are infrequent and seldom invalidating (81). Bone mineral density, however, is commonly decreased, and most adults are osteopenic or osteoporotic at 1 or more sites (89). 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 2 studies on morbidity and mortality have so far been published (42; 04). In the McGovern survey of 103 patients, 3 died from liver failure, 4 from oxygen-dependent pulmonary disease, and 3 from valvular heart disease; 4 suffered from coronary artery disease. In another cohort of 28 adult patients with type B, 3 died between 30 and 50 years of age, one from liver cirrhosis, one from cardiac insufficiency, one from respiratory failure; monoclonal gammopathy of undetermined significance was observed in 5 patients (34).
Data in a large Ashkenazi Jewish population suggest that the p.L304P variant (carrier frequency of about 1 out of 1000 in this population, see below) appears as a risk factor (odds ratio 9.4) for Parkinson disease (17). A smaller similar study has been conducted in samples from Chinese populations (15; 37). Thus far, no such study has been conducted in populations where p.R610del is the most frequent mutation.
Niemann-Pick disease type A/infantile neurovisceral acid sphingomyelinase deficiency. 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 deficient activity of acid sphingomyelinase in leukocytes. 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 in people or toys. Diffuse hypotonia was present but with apparently preserved muscular strength. Deep tendon reflexes were diminished or absent, which was associated with low nerve conduction velocities. Fundoscopic examination 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/chronic visceral acid sphingomyelinase deficiency. At the age of 4 years, severe hepatomegaly and moderate splenomegaly were discovered in a male with an uneventful infancy. He had normal neurologic and psychomotor development. Chest x-ray showed bilateral reticulonodular infiltrations. Diagnosis was initially made by histology on a liver biopsy and confirmed by enzyme assay at the age of 12 years. At that time, 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. He has a college level of education and runs a small business. At the age of 48 years and without the development of more severe symptoms, he only complains of dyspnea on exertion.
• Primary deficiency of the lysosomal acid sphingomyelinase [E.C. 188.8.131.52] resulting from mutations on the SMPD1 gene is the underlying cause.
• This deficiency leads to the progressive accumulation of sphingomyelin and secondarily of other lipids.
• Correlations between certain mutations and a neuronopathic or nonneuronopathic phenotype have been made.
Biochemistry and enzymatic findings. The primary deficiency in lysosomal acid sphingomyelinase resulting from pathogenic variants 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. 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, and of glycosphingolipids (78). Cerebral storage of sphingomyelin is only present in neurovisceral types. The brain tissue of type A patients also shows pronounced alterations of the ganglioside profiles, with accumulation of the minor GM2 and GM3 gangliosides (60).
Although a wealth of data are available regarding pathology and neuropathology in patients (12), 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 (31; 16). Neuronal death is a prominent feature of the disease, and a patterned death of Purkinje cells has been described (64). Calcium homeostasis was further shown to be altered, with reduced rates of calcium uptake via SERCA (19). Sphingomyelin-induced inhibition of plasma membrane calcium ATPase could be involved in neurodegeneration (54). Increased levels of a potentially apoptotic metabolite, the lysoderivative of sphingomyelin, sphingosylphosphorylcholine (05), have been reported in the brain of type A (but not B) patients, as well as in that of ASMKO mice (60). 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 plasma of type A and B patients (29; 55; 58; 09; 02) or dried blood spots.
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. 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 (80; 53). 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 (74; 67).
Genetics. The disease demonstrates an autosomal recessive pattern of 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. 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) (72). Currently, 346 variants have been described, among which 295 have been classified as disease-associated. Zampieri and colleagues compiled a list of mutations as well as corresponding references (93); more information can also be found at HGMD Professional 2022.1, which can be accessed at the following site:https://digitalinsights.qiagen.com/news/blog/clinical/new-content-release-hgmd-professional-2022-1/. In order to comply with the guidelines for mutation nomenclature from the Human Genome Variation Society (HGVS), mutations identified early and located downstream of nucleotide 142 (codon 48) currently appear with a codon number = p.(n+2) compared to the original description. This is due to the fact that 2 different cDNA reference sequences (GeneBank accession numbers NM_000543.4 and M81780.1) have been used, which differed in the length of a highly polymorphic hexanucleotide sequence, GCTGGC (p.L37_A38), located in exon 1 within the region encoding the signal peptide. The current nomenclature (RefSeq NM 000543.4) has been used in this article, with the “historical” one given in parentheses. Collectively, 3 variants, 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 variants have been described. In type B patients, p.R610del (R608del) is globally the most common variant (32; 79; 71; 61; 24; 43). It has so far always been correlated with a type B phenotype, even in the heteroallelic status, indicating that one copy of this variant is always associated with a chronic visceral form of acid sphingomyelinase deficiency (similar to the situation with the p.Asn409Ser (N370S) GBA1 mutation in Gaucher disease). Highly prevalent in North African type B patients (greater than 90% of alleles) (79), it is also very frequent in Spain (61% of alleles) (61), France (55%, but only 34% excluding patients of North African extraction) (Vanier unpublished data; 34), the Netherlands (52%) (24), and the United States (20% to 30%) (91). It has generally been considered as a “mild” mutation. Among other type B variants, p.R476W (R474W) and p.L139P (L137P) seem associated with a less severe form, but p.H144Y (H142Y) and p.K578N (K576N), which are frequent in Saudi Arabia, are associated with a severe form. p.A359D and are associated with a moderate to severe type B phenotype, which is highly prevalent in Chile (01). In China, p.R602H is the common type B variant (25). The variant p.Q294K (Q292K), initially described in patients from Central Europe, is clearly associated with late-onset neurologic involvement (53). The variant p.W393G (W391G), with a demonstrated Rumanian Gipsy origin, is relatively common in patients originating from the Western Balkanic region. The mutated p.W393G protein and resulting phenotypes have been well studied. A clinical variability was described within patients homozygous for this variant; a majority had systemic symptoms only, but some developed a late-onset neurologic disease (14; 48). In India, a large study revealed a significant prevalence of p.R742* (R740*) (59). The SMPD1 variant spectrum has also been reported in a cohort of 118 Chinese patients with acid sphingomyelinase deficiency, with a study of genotype/phenotype correlations (25).
• The disease is pan-ethnic but occurs more frequently in certain populations.
• Historically, more than half of the patients with type A were of Ashkenazi origin, but owing to genetic counseling and improved diagnosis in other populations, this is no longer true.
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 out of 80 and 1 out of 100. Type A seems much rarer in other populations; its incidence has been estimated to approximately 1 out of 560,000 living births in France (Vanier unpublished data).
The prevalence of type B is higher than that of type A in most countries but is 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 for the period 2000 to 2020 to approximately 1 out of 180,000 living births (Vanier unpublished data). The disease seems more frequent in North Africa, especially Tunisia (79; 65; 66), and also in Saudi Arabia (1:40,000 to 1:100,000) (22) and Turkey (71). 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 (53), but likely also China. In a recent cohort of 118 Chinese patients with acid sphingomyelinase deficiency, 16% were classified as type A, 64% as type B, and as many as 20% with the intermediate form (25).
• Sphingomyelinase deficiencies are genetically inherited following an autosomal recessive mode. Appropriate genetic counseling should be provided to individuals at risk.
• Prenatal diagnosis is possible by gene analysis provided that the mutant alleles have been identified in the index case and confirmed by a parental study, or by measurement of acid 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, one report of preimplantation diagnosis has been published, but this currently remains an exceptional procedure. 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 individuals with acid sphingomyelinase deficiency.
Niemann-Pick disease type A/infantile neurovisceral acid sphingomyelinase deficiency. Other conditions with hepatosplenomegaly and failure to thrive or psychomotor regression must be considered. Among the lipidoses, differential diagnoses of Wolman disease (severe form of 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/little-dysmorphic forms of GM1 gangliosidosis, need to be considered.
Niemann-Pick disease type B/chronic visceral acid sphingomyelinase deficiency. Various other causes of isolated splenomegaly or hepatosplenomegaly could be excluded if storage cells (foamy macrophages and/or sea-blue histiocytes) are found in bone marrow; such cells are suggestive of a lysosomal storage disease, but they are not specific for acid sphingomyelinase deficiency, nor always present. Differential diagnoses include, among lipidoses, Gaucher disease, Niemann-Pick disease type C (before the onset of neurologic symptoms), acid lipase deficiency (chronic form, cholesterol ester storage disease), and also glycogen storage diseases.
Chronic neurovisceral acid sphingomyelinase deficiency. Some cases with the (rare) intermediate forms may be confused with Niemann-Pick type C or Gaucher type 3.
• Acid sphingomyelinase activity (leukocytes, dried blood spots)
• SMPD1 gene sequencing
• For screening/follow-up: lysosphingomyelin and lysosphingomyelin-509/PPCS biomarkers (plasma)
The diagnosis of acid sphingomyelinase deficiency is established by demonstration of deficient acid sphingomyelinase activity in leukocytes (or lymphocytes), dried blood samples, or in cultured skin fibroblasts (from which a much higher level of activity can be demonstrated) (41). The choice of a specific substrate is critical. Sphingomyelin radioactively labeled on the choline moiety (natural substrate) is the gold standard, but its use is on the wane. Methods using a short-chain fatty acid sphingomyelin analogue and detection by tandem mass spectrometry (allowing enzyme determination on dried blood spots) have a good specificity and are currently recommended (41). Multiplex enzyme assays kits using this principle for simultaneous diagnosis of 6 lysosomal storage diseases are commercialized and can also be used for neonatal screening (85). The synthetic fluorogenic substrate 6-hexadecanoylamino-4MU-phosphorylcholine has a low sensitivity and is less reliable. 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 (53).
SMPD1 molecular genetic testing is increasingly becoming the preferred test for acid sphingomyelinase deficiency, but the diagnosis can only be established if biallelic pathogenic variants have been identified. In other cases (ie, variants of uncertain significance, allele segregation not established), the functional test, namely demonstration of a deficient activity of acid sphingomyelinase, is required to confirm the diagnosis. Identification of mutations is essential for genetic counseling and heterozygote detection in blood relatives. Genotyping may also help to predict a phenotype when the diagnosis is made in a young child (41). Of note, for SMPD1, it is particularly important that reports of genetic tests include the reference sequence number used (more information can be found in “genetics” below).
Several plasma biomarkers show abnormalities. They can constitute a good first orientation test before measuring enzyme activity. Plasma chitotriosidase activity is generally moderately elevated, but this finding is unspecific. Sensitive and more specific plasma biomarkers have been discovered in recent years. Lysosphingomyelin (lyso-SM) and the so-called “lysosphingomyelin-509”(lysoSM-509), now identified as N-palmitoyl-O-phosphocholine-serine (PPCS), are significantly elevated in acid sphingomyelinase deficiency (18; 29; Pettazoni et al 2017; 58; 09; 83; 35; 70), as well as the oxysterols cholestane-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) (28; 62), and the bile acid N-(3β,5α,6β-trihydroxycholan-24-oyl)glycine (TCG) (26). It is, however, important to remember that lysoSM-509/PPCS, C-triol, 7-KC, and TCG are also elevated in Niemann-Pick C (NPC) and C-triol or 7-KC in acid lipase deficiencies and some nonlysosomal diseases. The most specific plasma biomarker of acid sphingomyelinase deficiency to date is lysosphingomyelin (the deacetylated form of sphingomyelin, also named sphingosyl-phosphoryl-choline). A marked elevation of lyso-SM only occurs in acid sphingomyelinase deficiency, and not in Niemann-Pick C. Plasma lyso-SM levels have been used in follow-up of enzyme replacement therapy trials (10; 91), and a pilot study suggests that they are positively associated to the degree of clinical severity of the patients (02). Multiplex MS/MS assays have been developed, which allow simultaneous measurement of lyso-SM, PPCS, lyso-Gb1 (best biomarker for Gaucher disease), lyso-Gb3, and other lyso-glycosphingolipids. Such panels have proven useful in screening of sphingolipidoses and Niemann-Pick C. Striking elevation of lyso-Gb1 allows quick differential diagnosis of Gaucher disease, whereas a marked elevation of both lyso-SM and PPCS is the signature of acid sphingomyelinase deficiency, but not that of Niemann-Pick C.
Although not needed nor recommended for the diagnosis of acid sphingomyelinase deficiency, a bone marrow biopsy/aspirate may have been performed, due to the suspicion of a malignancy in a patient with unexplained splenomegaly. Typically, bone marrow of acid sphingomyelinase deficiency patients displays foamy macrophages (“Niemann-Pick cells”) and/or sea-blue histiocytes, but similar storage cells can be observed in other diseases, such as Niemann-Pick C, acid lipase deficiency, GM1-gangliosidosis. Besides, less experienced examiners may not make a difference between Gaucher cells and Niemann-Pick cells.
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) (44).
Besides precise assessment of spleen and liver volume, complementary evaluation following initial diagnosis should include an ophthalmologic examination, a comprehensive neurologic evaluation, a chest radiograph, and, in patients old enough to perform the test, pulmonary function testing. There is not always a strong correlation between radiologic findings and the results of pulmonary function tests; for correct evaluation, both are necessary, together with the clinical status of the patient; the most common findings in patients with functional pulmonary disease as low forced vital capacity and diffusing capacity of the lung for carbon monoxide (46; 40). 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 (88; 38). Depending on the clinical status and the examination of the skeleton, a DEXA scan could also be considered (89). If not already done, baseline measurements of the plasma biomarkers lyso-SM and PPCS/lyso-SM509 are recommended.
• To date, management of all types of acid sphingomyelinase deficiency is still essentially symptomatic. This may change in the near future.
• Clinical trials of enzyme replacement therapy using olipudase alfa have resulted in significant improvements in patients with the chronic visceral form (87; 91; 10), and long-term extension studies are pursued. Olipudase alfa has been approved by regulatory agencies in the European Union, Japan, and the United States. A compassionate use program is ongoing in some countries.
• A consensus guideline of recommended routine clinical assessments necessary for monitoring the multisystemic manifestations across the spectrum of acid sphingomyelinase deficiency phenotypes, which also includes options for treatment, interventions, and lifestyle changes, has been published (85).
• Information and support to families can be obtained through nonprofit organizations devoted to inherited metabolic diseases or lysosomal storage diseases. Organizations specific to Niemann-Pick diseases exist in many countries around the world. More information can be accessed at the following site:https://www.inpda.org.
• Genetic counseling should be made available to family members and to adult patients.
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 diffusing capacity of the lung for carbon monoxide for old enough patients), as well as liver function and fasting lipid profile. Guidelines of recommended routine clinical assessments have been proposed for all types of acid sphingomyelinase deficiency (85), or specifically for general care and monitoring of type B (13; 38). Attempts have also been made to define criteria leading to a stratification of patients with type B by degree of disease severity (38).
Thrombocytopenia may lead to bleeding. Total splenectomy should be a very last resort, as it has been shown to exacerbate the interstitial pulmonary disease and the liver disease, likely through increased accumulation of sphingomyelin and ancillary lipids.
In some patients, liver enlargement may evolve towards fibrosis and cirrhosis, with a highly variable rate of progression. Chronic liver disease must, therefore, be closely monitored because (rare) cases of fulminant liver failure have been reported. Successful liver transplantation has been reported in a few patients with advanced chronic liver disease.
Some patients with symptomatic pulmonary disease (including some children) may require various levels of oxygen therapy. Pulmonary lavage has been proposed in patients with severe respiratory disease but is controversial (65). It may have a temporary effect, but inflammatory cells are likely to repopulate the airways. Three patients (one of whom had a previous liver transplant) received a lung transplantation, with limited follow-up in the 2 surviving patients (11; 36; 52). A favorable 2-year follow-up was reported for two additional patients (77; 49).
Many type B patients have hypercholesterolemia, and adults should be treated with concomitant monitoring of their hepatic function.
Current status of specific enzyme replacement therapy. Patients with chronic visceral acid sphingomyelinase deficiency (Niemann-Pick type B) 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 ASMKO mice. It, however, took more than a decade before a phase 1 monocentric clinical trial with escalating doses of olipudase alfa 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" (45). A phase 1b (within-patient dose escalation) in 5 adult patients has provided further safety data and efficacy data after 30 months treatment. Positive clinical findings have been reported, including reduction in liver/spleen volumes, improved lung-diffusing capacities, and improvement in dyslipidemia (90; 87; 75). Two separate multicenter clinical trials have further been conducted in adult and pediatric patients. A phase 1/2 open label, ascending dose was conducted in 20 children over a 64-week study period (NCT02292654); one-year results showed comprehensive improvements across a range of clinically relevant endpoints, including a 49% reduction in spleen size and a 33% increase of diffusing capacity of the lung for carbon monoxide (DLCO) (27; 10). Results from the 52-week primary analysis period of a randomized, double-blind, ascending dose placebo-controlled phase 2/3 study (NCT02004691) involving 36 adult type B patients have been published (91). The 2 independent primary efficacy endpoints, DLCO and spleen volume, were met (40% difference between olipudase alfa vs. placebo for spleen volume, 19% difference for predicted DLCO). Treatment outcomes also favored olipudase alfa for liver volume and platelets levels. All treatment-related adverse events were mild to moderate in severity. All patients continue receiving olipudase alfa in a long-term extension study (NCT02004704). Treatment with olipudase alfa has now been approved by regulatory agencies in Japan, the European Union, and the United States. A compassionate use program (NCT04877132) is ongoing in some countries (38).
Hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation has shown no evidence of neurologic improvement in patients with infantile neurovisceral acid sphingomyelinase deficiency (type A) or severe chronic neurovisceral acid sphingomyelinase deficiency (50; 47). Although it significantly improved the lipid storage in one patient with chronic visceral acid sphingomyelinase deficiency (type B), hematopoietic stem cell 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 have been 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.
An extensive number of studies towards neural progenitor injections and gene therapy have also been conducted in the ASMKO mouse (65; 66; 68). AAV-mediated hepatic expression of acid sphingomyelinase had a profound effect on the reticuloendothelial system organs, but not on the brain. However, by intracerebral or, better, intracerebroventricular gene transfer, a remarkable improvement of the cerebral pathology and of the lifespan was observed. A first safety study of AAV2-mediated human acid sphingomyelinase (hASM) in the nonhuman primate brain revealed an inflammatory reaction. Encouraging data have, however, been obtained by cerebellomedullary cistern injection of AAV-9hASM (63). 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.
The issue of pregnancy is applicable to women with chronic visceral acid sphingomyelinase deficiency (Niemann-Pick type B). 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 women with Niemann-Pick type B are uncomplicated. There is a single report of fatal postpartum hemorrhage in literature. 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 from Orphazyme, Orchard Therapeutics, and Sanofi Genzyme as a member of scientific advisory boards and consulting fees from Orchard Therapeutics.See Profile
Erika Augustine MD MS
Dr. Augustine of Kennedy Krieger Institute, Johns Hopkins University, and University of Rochester Medical Center received consulting fees from Amicus Therapeutics, Exicure, and Taysha Gene Therapies, a clinical trial agreement as Central Rater from Neurogene Inc, and an honorarium as a member of the Data Safety and Monitory Board for PTC Therapeutics.See Profile
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