05 November 2022: Articles
Compound Heterozygote Mutation in the Gene Leading to Nieman-Pick Disease Type A
Challenging differential diagnosis, Rare disease
Alja Kavčič1AEF*, Matjaž Homan2E, Milanka Živanović3E, Maruša Debeljak4DE, Tita Butenko5E, Ana Drole Torkar6E, Mojca Žerjav Tanšek6E, Sara Bertok6E, Tadej Battelino6E, Urh Groselj 6ABDEFGDOI: 10.12659/AJCR.937220
Am J Case Rep 2022; 23:e937220
Abstract
BACKGROUND: Niemann-Pick disease (NPD) type A is an autosomal recessive lipid storage disorder caused by acid sphingomyelinase deficiency due to a mutation in the SMPD1 gene. Type A is the most severe phenotype of NPD, with early onset in infancy and unfavorable outcome in early childhood.
CASE REPORT: An 11-month-old boy with hepatosplenomegaly, elevated liver transaminases, and faltering growth was admitted to our hospital for further assessment of potential liver disease. He had severe generalized muscular hypotonia, muscular hypotrophy, reduced muscular strenght, joint laxity, weak deep tendon reflexes, and severe motor developmental delay. Leukodystrophy was seen on the brain MRI, and brainstem auditory evoked potentials were characteristic for auditory neuropathy. A chest X-ray showed signs of interstitial lung disease, which was not further evaluated due to absence of respiratory distress. Liver biopsy histopathologic findings were indicative for lipid storage disease. Genetic analysis showed that the patient is a compound heterozygote in the SMPD1 gene – (NM_000543.5): c.573delT p.(Ser192Alafs*65), which was inherited from the mother and c.1267C>T p.(His423Tyr) was inherited from the father. Both variants were previously individually reported in NPD type A and B. The clinical phenotype in our patient was characteristic of NPD type A, with an early onset and a rapidly progresive neurodegeneration. The patient was included in multidisciplinary follow-up, providing him symptomatic treatment and support.
CONCLUSIONS: We present a case of NPD type A caused by a rare compound heterozygote mutation in the SMPD1 gene. Most clinical findings and the disease course were typical for NPD type A, except for bilateral auditory neuropathy, which seems to be an uncommon finding in this phenotype and could be underestimated due to infrequent testing for auditory dysfunction.
Keywords: Genetics, Neurodegenerative Diseases, Niemann-Pick Disease, Type A, Rare Diseases, SMPD1 Protein, Human, Child, Preschool, Humans, Male, Heterozygote, Lipids, Mutation, Niemann-Pick Diseases, Pick Disease of the Brain, Sphingomyelin Phosphodiesterase
Background
Niemann-Pick disease (NPD) type A is a lipid storage disorder caused by acid sphingomyelinase (ASM) deficiency [1]. The ASM lysosomal enzyme deficiency resulting from mutations in the
Case Report
An 11-month-old boy presented for gastrointestinal evaluation due to elevated liver transaminase levels. He was a second-born child. His older sibling had a history of vesicoureteral reflux but was otherwise healthy. Two members on the mother’s side of the family had idiopathic transient hyperbilirubinemia in childhood. The pregnancy was uneventful, prenatal ultrasound showed polyhydramnion, and the child was born at term with vaginal delivery (birth weight of 3810 g and length 53 cm). The Apgar score was 9/10. Due to mild respiratory distress, he needed transient oxygen therapy without ventilatory support. He had mild transient indirect hyperbilirubinemia, not meeting the criteria for phototherapy.
Faltering growth and motor delay with hypotonia and nystagmus were identified at 3 months of age. A brain MRI showed delayed myelination and the patient was followed by a pediatric neurologist. One month later, he had an acute gastroenteritis, and higher liver transaminase levels (AST 1.38 mcgkat/l, reference value <0.58 mcgkat/l and ALT 1.08 mcgkat/l, reference value <0.74 mcgkat/l) were noted. Gama-GT was normal (0.4 mcgkat/l). At the age of 10 months, he had significant hepatosplenomegaly and transaminase levels further increased (AST 3.77 mcgkat/l, ALT 4.40 mcgkat/l, gama-GT 0.85 mcgkat/l); therefore, he was admitted to our Pediatrics’ Gastroenterology Department. Liver transaminases were persistently elevated (AST 6.44 mcgkat/l, ALT 5.28 mcgkat/l, gama-GT 0.9 mcgkat/l) and bilirubin levels were normal. He had mild normocytic anemia (Hb 101 g/l), normal platelet count, and normal coagulation. Proteinogram and immunoglobulin levels were normal. He had increased alpha-fetoprotein level (up to 27.2 kU/l), increased total cholesterol (5.2 mmol/l, reference value <3.9 mmol/l), decreased HDL (0.6 mmol/l, reference value >1 mmol/l), increased LDL (4.9 mmol/l, reference value <2.6 mmol/l), and increased triglycerides (3.4 mmol/l, reference value <1.7 mmol/l). Celiac disease was excluded, with normal levels of t-TG IgA and IgA. Blood gas analysis, acylcarnitines, plasma amino acids, urine organic acids, and ammonia were normal. Diagnostic tests for liver diseases (alpha-1-antitripsin, ceruloplasmin, EBV and CMV antibodies, hepatitis viruses A, B and C, autoimmune hepatitis antibodies) were all negative. Abdominal ultrasound showed hepatosplenomegaly (liver size 109×104×82 mm, spleen longitudinal size 113 mm) without signs of portal hypertension. The beta-glucosidase level was normal and chitotriosidase was moderately increased (4620 nmol/ml/h, reference range 3–65 nmol/ml/h). Liver biopsy was performed. Histological evaluation showed numerous enlarged histiocytes with intracytoplasmic inclusions both in hepatic lobules and portal tracts (Figure 1A). Hepatocytes and biliary epithelia appeared swollen, with pale eosinophilic cytoplasm. Ultrastructural analysis showed accumulation of concentrically laminated myeloid structures in hepatocytes, Kupffer cells, endothelium, biliary epithelial cells, and fibroblasts (Figure 1B), which combined with histological findings suggested lipid storage disease. Due to liver biopsy results, we conducted targeted clinical and genetic tests for NPD. Acid sphingomyelinase level was unmeasurably low (<0.4 mcgmol/h/l) and lyso-SM-509 was increased (10.9 ng/ ml, reference value <0.01 ng/ml).
For genetic analysis, next-generation sequencing (NGS) was performed. We reached 99.9% at least 10× coverage for a patient. The selected core panel for hepatopathy was used for filtering. Genetic analysis showed that patient was compound heterozygote in the
During the hospitalization, we observed dysphagia and consequent inadequate caloric intake, which was improved with dietetic counseling. Neurologically, the boy had severe generalized muscular hypotonia, moderate muscular hypotrophy, and reduced muscular strenght, joint laxity, weak deep tendon reflexes, and severe motor developmental delay (motor quotient 50). Continuous cardiac and respiratory function monitoring in sleep and EEG were normal. Brainstem auditory evoked potentials showed auditory neuropathy with bilaterally increased auditory thresholds. Cardiac ultrasound showed mild left ventricular hypertrophy, with normal systolic and diastolic function. Vision acuity and fundoscopy were normal. A chest X-ray showed signs of interstitial lung disease, which was not further investigated due to absence of respiratory distress. The patient was included in multidisciplinary team follow-up for symptomatic treatment and support.
Discussion
The primary organs affected in all ASM-deficient patients are the spleen and liver [3]. Hepatosplenomegaly was also the most prominent early clinical finding in our patient. Foam cells are found in various organs and bone marrow of patients with both type A and B NPD, and in our patient numerous foamy histiocytes (Niemann-Pick cells) were found on the liver biopsy. Quantifying the ASM activity in circulating leukocytes or cultured skin fibroblasts is the standard confirmatory diagnostic procedure [3]. ASM activity in our patient was undetectably low (<0.4 mcgmol/h/l). ASM is produced from a single gene (
The patient had normal neurodevelopment up to 3 months of age, which is consistent with other reports of NPD cases [7]. Bilateral pyramidal signs with increasing spasticity and loss of deep tendon reflexes are the most prominent neurologic signs described in the literature. Our patient had diminished deep tendon reflexes, but spasticity had not evolved by the age of 17 months. Brain imaging showed leukodystrophy, which is also typical for NPD type A according to previous studies [2,3]. Brainstem auditory evoked potentials were distinctive for auditory neuropathy. Hearing abnormalities were not yet described in NPD type A, but a study from King et al [8] reported a prevalent auditory dysfunction in patients with NPD type C1, with clinically significant high-frequency hearing peripheral hearing loss and a progressive course. Ophthalmological exam results in our patient were normal, although it is known that a cherry-red spot is present in the macula in approximately 50% of these infants [3].
A chest X-ray showed signs of interstitial lung disease, which is rare but reported in various types of NPD, most frequently in type B [9]. Niemann-Pick cells accumulate in the alveolar septa, bronchial walls, and pleura, leading to progressive restrictive lung disease with decreased diffusion capacity and potential oxygen dependence. Our patient had no signs of respiratory distress, and continuous monitoring of respiratory function in sleep was normal; therefore, this finding was not further investigated [10].
Laboratory results showed anemia, dyslipidemia, elevated liver transaminases, and moderately increased chitotriosidase. The platelet count was normal, although thrombocytopenia is the most common finding according to some studies [11]. All abnormal laboratory results in our patient were previously described in NPD type A [11,12].
Unfortunately, there is no treatment available for NPD type A; therefore, management is symptomatic [3]. Final stages of the disease include loss of spontaneous movement, chronic respiratory failure, and recurrent respiratory infections. Life expectancy is 1.5–3 years of age [7]. Assessment is complex due to the diverse spectrum of problems.
Conclusions
Our patient, diagnosed with NPD type A, was found to be a compound heterozygote with 2 genetic variants of the
References:
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2.. Vanier MT, Niemann-Pick diseases: Handbook of Clinical Neurology, 2013; 1717-21
3.. Schuchman EH, Desnick RJ, Types A and B Niemann-Pick disease: Mol Genet Metab, 2017; 120(1–2); 27-33
4.. Schuchman EH, Levran O, Pereira LV, Desnick RJ, Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1): Genomics, 1992(12); 197-205
5.. Lee CY, Krimbou L, Vincent J, Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol: Hum Genet, 2003(112); 552-62
6.. Sikora J, Pavlu-Pereira H, Elleder M, Seven novel acid sphingomyelinase gene mutations in Niemann-Pick type A and B patients: Ann Hum Genet, 2003; 67(1); 63-70
7.. McGovern MM, Aron A, Brodie SE, Natural history of type A Niemann-Pick disease: Possible endpoints for therapeutic trials: Neurology, 2006; 66; 228-32
8.. King KA, Gordon-Salant S, Yanjanin N, Auditory phenotype of Niemann-Pick disease, type C1: Ear Hear, 2014; 35(1); 110-17
9.. Guillemot N, Troadec C, De Villemeur TB, Lung disease in Niemann-Pick disease: Pediatr Pulmonol, 2007; 42(12); 1207-14
10.. von Ranke FM, Pereira Freitas HM, Mançano AD, Pulmonary involvement in Niemann-Pick disease: A state-of-the-art review: Lung, 2016; 194(4); 511-18
11.. Hollak CEM, de Sonnaville ESV, Cassiman D, Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: Disease spectrum and natural course in attenuated patients: Mol Genet Metab, 2012; 107; 526-33
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