Compound Heterozygote Mutation in the SMPD1 Gene Leading to Nieman-Pick Disease Type A.

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.

De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH).

Familial Progressive Hyper- and Hypopigmentation is a pigmentary disorder characterized by a mix of hypo- and hyperpigmented lesions, café-au-lait spots and hypopigmented ash-leaf macules. The disorder was previously linked to KITLG and various mutations have been reported to segregate in different families. Furthermore, association between KITLG mutations and malignancies was also suggested. Exome and SANGER sequencing were performed for identification of KITLG mutations. Functional in silico analyses were additionally performed to assess the findings. We identified a de novo mutation in exon 4 of KITLG gene causing NM_000899.4:c.[329A>T] (chr12:88912508A>T) leading to NP_000890.1:p.(Asp110Val) substitution in the 3rd alpha helix. It was predicted as pathogenic, located in a conserved region and causing an increase in hydrophobicity in the KITLG protein. Our findings clearly confirm an additional hot spot of KITLG mutations in the 3rd alpha helix, which very likely increases the risk of malignancies. To our knowledge the present study provides the strongest evidence of association of the KITLG mutation with both Familial Progressive Hyper- and Hypopigmentation and malignancy due to its' location on somatic cancer mutation locus. Additionally we also address difficulties with classification of the unique phenotype and propose a subtype within broader diagnosis.

Possible pitfalls in the diagnostic of progressive multifocal leukoencephalopathy.

The most accurate diagnosis of clinically suspected progressive multifocal leukoencephalopathy (PML) is made by neuronavigated needle brain biopsy and microscopic examination of the specimen confirming typical morphological features of the disease and, additionally, using immunohistochemistry (IHC) for detection of early viral proteins of the etiologic agent - polyoma virus JC (JCV). Due to the small biopsy volume, this approach can sometimes fail to confirm the clinical diagnosis of PML, as demonstrated by the presented clinical case. To check the reliability of using only IHC, we additionally tested 6 archival cases from our institute using IHC, in-situ hybridization (ISH) and real-time polymerase chain reaction (PCR). In the presented case, both biopsy and autopsy material were tested, in three archival cases only biopsy material and in the remaining cases post-mortem brain tissue was available. IHC (Anti-SV40 T antigen, mAb Pab416) was negative in 3 samples, in another 3 fewer than 10 cells per one ×20 microscopic field were positive. In our study, ISH proved to be a more sensitive method for JCV detection than IHC, being positive in all cases. Out of 7 tested specimens, realtime PCR failed to confirm the presence of JCV in 1 specimen, which was the oldest brain autopsy of an AIDS patient. Our study demonstrated that, especially when confronted with borderline clinical suspicion of PML and when only a small biopsy specimen is available, a combination of at least two different methods for JCV detection should be considered, preferably IHC with one of the available molecular methods.