Unusual presentation of Kelley-Seegmiller syndrome.

Female carriers of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency have somatic cell mosaicism of HPRT activity and are healthy. We report a 50-year-old woman without gout or nephrolithiasis. She was never on allopurinol. Normal serum uric acid concentrations, increased plasma hypoxanthine, and xanthine were found. HPRT activity in erythrocytes was surprisingly low: at 8.6 nmol h(-1) mg (-1) haemoglobin. Mutation analysis revealed a heterozygous HPRT gene mutation, c.215A > G (p.Tyr72Cys). Assessment of X-inactivation ratio has shown that > 75% of the active X-chromosome bears the mutant allele and could explain these unusual, previously undescribed findings.

A case of excessive autophagocytosis with multiorgan involvement and low clinical penetrance.

An autopsy and microscopic analyses of a 74-year-old female with a clinical history of cardiac hypertrophy and hypertension disclosed a pronounced distension of lysosomal compartment with signs of excessive autophagocytosis, predominantly in cardiomyocytes, hepatocytes and smooth muscle cells of the small intestine. The histological storage pattern did not correspond to the usual changes seen in defined lysosomal storage disorders. The amount of age-related lipopigment was low in all tissues. Confocal microscopy of liver tissue samples documented a progressive loss of mitochondrial epitopes in the distended lysosomal compartment along the porto-central axis of hepatic lobules. The possibility to detect subunit c of mitochondrial ATP synthase (SCMAS) indicated extensive intra-lysosomal degradation of mitochondria, both in hepatocytes and smooth muscle cells. The SCMAS epitope can thus be considered a valuable immunohistochemical marker of autophagocytic mitochondrial degradation. The distended lysosomes also displayed tissue specific ubiquitination. Absence of immuno-detectable p62 protein excluded aggresome formation. An inherent dysfunction of the late endosomal/lysosomal LAMP2 protein (Danon disease), was excluded on the basis of LAMP2 gene sequence analysis and LAMP2 protein levels. Whether the observed process reflects a primary dysregulation of the constitution of the autophagosomal membrane or was induced by defects in other cellular components, remains unanswered. Whatever mechanism involved, the findings should be considered relevant in differential diagnostics, despite their low clinical penetrance, should be registered and thus rendered available for future definition.

Subclinical course of adult visceral Niemann-Pick type C1 disease. A rare or underdiagnosed disorder?

We present the third case of Niemann-Pick disease type C without neurological symptoms. The patient was a 53-year-old woman without significant prior health problems who died of acute pulmonary embolism. Autopsy findings of hepatosplenomegaly, lymphadenopathy and ceroid-rich foam cells raised the suspicion of the visceral form of acid sphingomyelinase deficiency (Niemann-Pick disease type B; NPB) or a much rarer disorder, variant adult visceral form of Niemann-Pick disease type C (NPC). To verify the histopathological findings, SMPD1, NPC1 and NPC2 genes were analysed. Two novel sequence variants, c.1997G>A (S666N) and c.2882A>G (N961S) were detected in the NPC1 gene. No pathogenic sequence variants were found either in the SMPD1 gene mutated in NPB or in NPC2 gene. The pathogenicity of both NPC1 variants was supported by their location in regions important for the protein function. Both variations were not found in more than 300 control alleles. Identified sequence variations confirm the diagnosis of the extremely rare adult visceral form of Niemann-Pick disease type C, which is otherwise dominated by neurovisceral symptoms. Although only three patients have been reported, this (most probably underdiagnosed) form of NPC should be considered in differential diagnosis of isolated hepatosplenomegaly with foam cells in adulthood.