Clinical Description
Although the phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum, individuals with the severe early-onset infantile neurovisceral phenotype (NPD-A) can be distinguished from those with the intermediate chronic neurovisceral phenotype (NPD-A/B) and chronic visceral ASMD (NPD-B) based on clinical presentation.
Infantile Neurovisceral ASMD (NPD-A)
Feeding problems / growth. Feeding problems are severe, resulting in failure to thrive. Initially, feeding issues appear to result from early satiety because of gastric compression due to hepatosplenomegaly, but as the neurologic decline progresses, infants lose the ability to coordinate sucking and swallowing. Frequent vomiting can contribute to insufficient caloric intake. Linear growth is within the normal range during the first year, whereas weight attainment declines in the first year of life.
Gastrointestinal manifestations (in addition to vomiting) include constipation and diarrhea. Some infants have abdominal discomfort and gassiness which may result in irritability and sleep disturbance.
Liver manifestations. The first symptom in most children with NPD-A is hepatomegaly, which typically is noted by age three months [McGovern et al 2006]. Transaminases are persistently elevated. The hepatomegaly worsens with time; eventually, the liver becomes massive. Over time, infants with NPD-A can exhibit evidence of liver failure such as coagulopathy and ascites.
Splenic manifestations. Enlargement of the spleen is often noted by age three months. Blood counts can be abnormal, reflective of hypersplenism.
Pulmonary disease. On chest radiograph, affected infants have evidence of interstitial lung disease caused by storage of sphingomyelin in the pulmonary macrophages. Low pO2 on arterial blood gas determination is usually found later in the disease course. Frequent respiratory infections are common and respiratory failure can be a cause of death.
Ophthalmologic findings. Fundus examination reveals retinal changes at the time of diagnosis in most children. The accumulation of lipid in the retinal ganglion cells results in a white ring of lipid-laden neurons encircling the red, ganglion cell-free fovea and manifests as either a macular halo or a cherry-red macula, depending on the degree of opacity and diameter of the white annulus surrounding the fovea. Although a classic cherry-red spot may not be present early in the disease course, all children with NPD-A develop one with time.
Neurologic findings. The neurologic examination at the time of presentation can be normal except for slight hypotonia. Hypotonia is progressive and deep tendon reflexes are lost with time. Cranial nerve function remains intact.
Psychomotor development does not progress beyond the 12-month level for any domain and skills are lost with disease progression [McGovern et al 2006]. Developmental age usually does not progress beyond age ten months for adaptive behavior, 12 months for expressive language, nine months for gross motor skills, and ten months for fine motor skills.
Neurologic deterioration is relentless, and most children succumb before the third year. The most common immediate cause of death is respiratory infection [Author, personal observation].
Chronic Neurovisceral ASMD (NPD-A/B)
Individuals with ASMD who survive early childhood but have progressive and/or clinically significant neurologic manifestations have chronic neurovisceral ASMD (NPD-A/B). Most individuals with NPD-A/B survive into adulthood. The extent of visceral organ involvement is variable, similar to NPD-B.
Liver dysfunction. The degree of hepatosplenomegaly ranges from mild to massive. Transaminases are often elevated, and some individuals have histologic abnormalities ranging from hepatic fibrosis to frank cirrhosis [Thurberg et al 2012]. Similar to NPD-B disease, liver failure may require liver transplantation [McGovern et al 2013].
Splenic involvement. Hypersplenism leads to secondary thrombocytopenia and can cause acute abdominal pain.
Pulmonary involvement. Interstitial lung disease may result in oxygen dependence and severe limitations of activity.
Neurologic signs. In individuals with NPD-A/B, the neurologic findings can include cerebellar signs and nystagmus [Obenberger et al 1999], extrapyramidal involvement, intellectual disability, and psychiatric disorders. In a review of 64 persons initially classified as having NPD-B, Wasserstein et al [2006] determined that 19 (30%) had neurologic abnormalities. Of the 19, 14 (22%) had minor and non-progressive findings and five (8%) had global and progressive findings (peripheral neuropathy, retinal abnormalities) with onset between ages two and seven years. The five with progressive findings had the pathogenic variant.
Growth. Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with ASMD and can result in significant short stature in adulthood. In one study, the mean Z scores for height and weight were −1.24 (29th centile) and −0.75 (34th centile), respectively, and skeletal age in children under age 18 years was delayed by an average of 2.5 years [Wasserstein et al 2003]. Short stature and low weight are correlated with large organ volumes, delayed bone age, and low serum IGF-1 concentrations.
Hyperlipidemia. Low serum concentration of high-density lipoprotein cholesterol (HDL-C) is accompanied by hyperlipidemia characterized by hypertriglyceridemia and elevated serum concentration of low-density lipoprotein cholesterol (LDL-C). Lipid abnormalities are evident from the earliest age studied and contribute to cardiac disease.
Coarse facial features are present in a subset of individuals with NPD-A/B.
Osteopenia or osteoporosis may lead to an increase in fractures.
Chronic Visceral ASMD (NPD-B)
NPD-B, later in onset and milder in manifestations, is characterized by hepatosplenomegaly, liver dysfunction, progressive hypersplenism, worsening atherogenic lipid profile, and gradual deterioration in pulmonary function [Wasserstein et al 2004, McGovern et al 2008]. Most individuals with NPD-B survive into adulthood.
Liver dysfunction. Liver enlargement is common. The degree of hepatosplenomegaly ranges from mild to massive. Many individuals with NPD-B have elevated transaminases and some have histologic abnormalities ranging from hepatic fibrosis to frank cirrhosis [Thurberg et al 2012]. In rare instances, liver failure has required liver transplantation [McGovern et al 2013].
Splenic involvement. Those with significant organomegaly have hypersplenism with secondary thrombocytopenia. Infarction of the spleen can cause acute abdominal pain.
Pulmonary involvement is common in affected individuals of all ages [Minai et al 2000, Mendelson et al 2006]. Clinical impairment ranges from none to oxygen dependence and severe limitations of activity. Most affected individuals have evidence of interstitial lung disease on chest radiographs and thin-section CT. While most individuals have progressive gas exchange abnormalities, the extent of the radiographic findings may not correlate with impairment of pulmonary function.
Calcified pulmonary nodules can also be seen.
Ophthalmologic manifestations. Up to one third of individuals with NPD-B have a macular halo or a cherry-red macula. Most have no evidence of progressive neurologic disease; the presence of a macular halo or a cherry-red macula is not an absolute predictor of neurodegeneration [McGovern et al 2004b] and there do not appear to be any clinical consequences with respect to visual function.
Growth. Abnormal linear growth and delayed skeletal maturation are common in children and adolescents and can result in significant short stature in adulthood. In one study, the mean Z scores for height and weight were −1.24 (29th centile) and −0.75 (34th centile), respectively, and skeletal age in children under age 18 years was delayed by an average of 2.5 years [Wasserstein et al 2003]. Short stature and low weight are correlated with large organ volumes, delayed bone age, and low serum IGF-1 concentrations.
Hyperlipidemia. Low serum concentration of HDL-C is common in NPD-B [McGovern et al 2004a]. In most individuals the low serum concentration of HDL-C is accompanied by hyperlipidemia characterized by hypertriglyceridemia and elevated serum concentration of LDL-C. Lipid abnormalities are evident from the earliest age studied.
Cardiac disease. Early coronary artery disease, identified in some adults with NPD-B, is presumably related to the dyslipidemia. Some individuals have valvular heart disease due to sphingomyelin deposition.
Osteopenia. Skeletal involvement is common in individuals with NPD-B. In one study, lumbar spine Z scores for children ranged from 0.061 to −4.879. Most adults with NPD-B had osteopenia or osteoporosis at one or more sites according to the WHO classification of bone marrow density [Wasserstein et al 2013]. Pathologic fractures have been reported.
Other. Calcifications in organs other than the lungs have been described, such as the adrenal glands. There are no known clinical consequences of these findings.
Pregnancy and childbirth. Pregnancy in a mildly affected woman has been reported, and 17 pregnancies monitored in women with a wide spectrum of clinical manifestations have been successful [McGovern, personal communication]. Most affected women, even those with significant pulmonary disease, can have normal pregnancies and childbirth. Hepatosplenomegaly does not usually pose a threat to fetal growth.
Genotype-Phenotype Correlations
The pathogenic variant appears to be neuroprotective; individuals with at least one copy of p.Arg610del will not develop neurologic manifestations and will have NPD-B disease. Individuals homozygous for p.Arg610del will have less severe disease than those with one copy in combination with a more severe variant [Wasserstein et al 2004]. In contrast to individuals with other pathogenic variants, individuals homozygous for the p.Arg610del pathogenic variant usually have normal height and weight, markedly less hepatosplenomegaly and bone age delay, and normal serum concentration of IGF-1. Lipid abnormalities occur with all genotypes, including homozygosity for the p.Arg610del pathogenic variant.
Some evidence suggests that the , , and pathogenic variants also result in a less severe form of NPD-B.
The and pathogenic variants, found most commonly in individuals from Saudi Arabia, lead to an early-onset severe form of the disease that is most consistent with the intermediate phenotype (NPD-A/B; chronic neurovisceral form) [Simonaro et al 2002].
The pathogenic variant, associated with intermediate phenotypes with later-onset neuronopathic disease (NPD-A/B), appears to be relatively common in individuals of Czech and Slovak heritage [Pavlů-Pereira et al 2005].
Homozygosity or compound heterozygosity for some combination of the common SMPD1 pathogenic variants observed in individuals with NPD-A predicts the type A phenotype. For example, any combination of the , , or p.Phe333SerfsTer52 variants results in NPD-A.
Prevalence
The estimated prevalence of ASMD is 1:250,000 [Meikle et al 1999]. However, population-wide screening has not been performed, and this and other estimates are based on the number of clinically diagnosed individuals referred for biochemical and/or molecular confirmation. In Chile, screening of 1,691 healthy individuals for a common SMPD1 pathogenic variant, , found a heterozygote frequency of 1:105.7, predicting a disease incidence of 1:44,960 [Acuña et al 2016].
Pathogenic variants causing the severe neurodegenerative form of the disease (NPD-A) are more prevalent in the Ashkenazi Jewish population, in which the combined carrier frequency for the three common SMPD1 pathogenic variants (, , and ) is between 1:80 and 1:100. Carrier screening programs and the availability of prenatal testing have resulted in a low birth incidence in this population.
All forms of ASMD are pan ethnic. Genotype information on individuals with NPD-B from 29 different countries has been reported [Simonaro et al 2002].