Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2mutations in isolated AMRF features

Abstract

BackgroundAction myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy.To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features.MethodsIn the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons.ResultsA novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA).ConclusionsOur findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.

Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations

“…Immunostaining analyses of brain and kidney samples with an antibody specific for the C‐terminus of SCARB2 (LIMP II) showed that the protein was not severely decreased in case 1 (Figure ). On the other hand, the R121X mutation detected in case 2 (Figure ) was a type similar to those in cases reported previously . Such nonsense mutations generate premature translation termination codons (PTCs) and generally facilitate degradation of SCARB2 mRNA by nonsense‐mediated mRNA decay (NMD).…”

“…Finally, dementia (or cognitive decline), which has never been described in patients with AMRF or PME‐SCAB2 , was evident in the present two patients. It is important to note that marked dementia was evident in the final year of life in the 24‐year‐old woman who was diagnosed post mortem as having a ‘pigment variant of neuronal ceroid lipofuscinosis (Kufs' disease)’ .…”

Lysosomal integral membrane protein-2: A new player in lysosome-related pathology

“…Another study by Hopfner et al . examined a German family with AMRF, showing that three affected members who were homozygous for the SCARB2 mutation c.111delC also had a demyelinating peripheral neuropathy [65]. …”

“…Two of the affected members of the German AMRF family described by Hopfner et al . developed cardiomyopathy, which may be significant given this important finding, but further analyses are necessary to elucidate this connection [25,65]. …”

The progressive myoclonic epilepsies

“…It is an autosomal-recessive disease related to loss-of-function mutations in SCARB2 gene 14. The onset is in the second and third decades, but there is also a late-onset form, starting in the fifth and sixth decades and without renal failure 15 16.…”