Visceral symptoms as a key diagnostic sign for the early infantile form of Niemann–Pick disease type C in a Russian patient: a case report

Abstract

BackgroundNiemann–Pick disease type C is a rare metabolic disease characterized by progressive neurological deterioration with childhood onset, and often results in premature mortality. Niemann–Pick disease type C has an extremely heterogeneous clinical presentation with a wide range of visceral and neurological signs and symptoms that are not specific to the disease, and which progress over varied periods of time. The incidence and epidemiology of Niemann–Pick disease type C in Russia have not been characterized. We report the case of a Russian newborn with early-infantile onset Niemann–Pick disease type C who displayed prolonged neonatal jaundice and hepatosplenomegaly.Case presentationA 5-year-old white boy born to non-consanguineous Russian parents was originally diagnosed with galactosemia at the age of 2 months based on a raised blood galactose level. A galactose-free and lactose-free diet resulted in achievement of a normal galactose level, but hepatosplenomegaly and cholestatic signs persisted. Liver biopsy results hinted at possible Niemann–Pick disease type C, but differential diagnostic investigations for progressive familial intrahepatic cholestasis type 2 (Byler syndrome) indicated a heterozygous genotype suggestive of this disease. Further, progressive neurological symptoms prompted additional genetic analyses for possible Niemann–Pick disease type C, from which an as-yet unreported combination of known NPC1 gene mutations was identified, and a final diagnosis of Niemann–Pick disease type C was established. The patient subsequently developed typical neurological symptoms of early-infantile Niemann–Pick disease type C, including vertical supranuclear ophthalmoparesis and cerebellar ataxia. Miglustat therapy was initiated 2.5 years ago, and some improvements in movement and speech have since been observed.ConclusionsThis case illustrates the continued challenges associated with diagnosing Niemann–Pick disease type C based on the appearance of nonspecific cholestatic symptoms. Based on this case we recommend examination of all newborns and children who display unexplained cholestasis or isolated splenomegaly/hepatosplenomegaly during the first months of life for other signs of possible Niemann–Pick disease type C.

Severe demyelination in a patient with a late infantile form of Niemann‐Pick disease type C

“…Although the onset and progression in this case were similar to that seen in the severe infantile form, the disease form was more compatible with the late infantile form due to the age at death and the patient's disturbed eye movement and acquired ambulation . A recently developed drug miglustat has proven to be effective for similar infantile forms of NPC that involve disturbed ocular movement and ambulation …”

“…1,2 A recently developed drug miglustat has proven to be effective for similar infantile forms of NPC that involve disturbed ocular movement and ambulation. 3 Our patient harbored compound heterozygous mutations of the NPC1 gene, with the missense mutation T2108C (F703S) and the nonsense mutation C2348G (S813X), neither of which have been previously reported. The single nucleotide polymorphism (SNP) database includes a base change that causes an F703I amino acid change, but this variant has not been reported to be disease-causing.…”

Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis

“…In a recent epidemiologic study of 53 patients with NPC in the United Kingdom, 17 (32%) had a systemic presentation [24]. Systemic manifestations include neonatal cholestatic jaundice, sometimes progressing to fulminant liver failure, transient jaundice in the newborn period, isolated hepatomegaly or splenomegaly or both, and/or evidence of hypersplenism (decreased blood counts such as thrombocytopenia, leukopenia, or anemia related to enlarged spleen size) [1, 14, 24, 32, 33]. NPC should be strongly suspected in the neonate with cholestasis [34] and is one of several inherited metabolic disorders to be a recognized cause of fatal acute liver failure in the newborn or young child [35].…”

Rapid whole-genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann–Pick type C1 disease in a 7-week-old male with cholestasis

“…HPβCD is the only drug that has been proven to ameliorate neurodegeneration and prolong the life span of NPC1 mice ( Liu et al 2009 ) and thus far has shown promising results in a small cohort of older NPC1 patients (World 2017 posters). Diagnosis of NPC1 in infants before development of neurologic disease is uncommon ( Degtyareva et al 2016 ). A literature review identified only two prior cases of patients diagnosed with NPC in infancy who started miglustat therapy upon diagnosis.…”