Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.

Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. The pathogenicity of the mutation was tested in vitro, in mutant fibroblasts and skeletal muscle, and in a yeast model. A Pitrm1(+/-) heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Aβ-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aβ degradation and that impairment of its activity results in Aβ accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.Cariplo2011‐0526 ERCFP7‐322424 Swedish Research Council Helse Vest911810 Forening for muskelsyke Italian Ministry of HealthGR‐2010‐2306‐75

MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing

Background: Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor. Methods: We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions. Results: A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 μmol/L, normal <1.5 μmol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients. Conclusions: Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset α-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake

Multiple small hyperintense lesions in the subcortical white matter on cranial MR images in two Turkish brothers with cold-induced sweating syndrome caused by a novel missense mutation in the CRLF1 gene

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by excess sweating induced by cold exposure, camptodactyly and kyphoscoliosis. CISS is genetically heterogeneous. Deficiency of the CRLF1 or the CLCF1 gene function results in one of two clinically indistuinguishable disorders called CISS1 and CISS2, respectively. We present two Turkish brothers (22 and 13 years old) who had excess sweating induced by cold exposure, severe dorsal scoliosis, camptodactyly, reduced pain sensitivity and marfanoid habitus. The patients were homozygous and their parents heterozygous for a novel missense mutation c.413C>T (p.Pro138Leu) in CRLF1 gene. The cranial magnetic resonance imaging (MRI) of two patients also showed multiple small hyperintense lesions in the subcortical white matter. Similar MRI finding has also been reported in a Japanese woman with CISS1 and marfanoid habitus. The lesions found in the present cases showed no characteristic features. However, multiple small hyperintense lesions in subcortical white matter on T2 weighted and fluid attenuation inversion recovery (FLAIR) images may support the clinical diagnosis of CISS. (C) 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved

Novel SACS mutations identified by whole exome sequencing in a norwegian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

We employed whole exome sequencing to investigate three Norwegian siblings with an autosomal recessive spastic ataxia and epilepsy. All patients were compound heterozygous (c.13352T>C, p.Leu4451Pro; c.6890T>G, p.Leu2297Trp) for mutations in the SACS gene establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The clinical features shown by our patients were typical of this disorder with the exception of epilepsy, which is a rare manifestation. This is the first report of ARSACS in Scandinavian patients and our findings expand the genetic and clinical spectrum of this rare disorder. Moreover, we show that exome sequencing is a powerful and cost-effective tool for the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias

Cold-Induced Sweating Syndrome Is Caused by Mutations in the CRLF1 Gene

In 1978, Sohar et al. described a strikingly peculiar syndrome in two Israeli sisters. These young women responded to environmental temperatures of 18°C–7°C with profuse sweating on large segments on their back and chest. Both had additional abnormalities, including a high-arched palate, nasal voice, depressed nasal bridge, inability to fully extend their elbows, and kyphoscoliosis. We have observed this disorder in two Norwegian brothers. Genomewide screening in the two families, followed by saturation marker studies and linkage analysis, identified a 1.4-Mb homozygous candidate region on chromosome 19p12. The maximum multipoint LOD score was 4.22. In both families, DNA sequencing of 25 genes within the candidate region identified potentially deleterious CRLF1 sequence variants that were not found in unaffected control individuals. Our findings confirm that the cold-induced sweating syndrome is an autosomal recessive disorder that is probably caused by impaired function of the CRLF1 gene, and they suggest important developmental functions for human CRLF1

ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic?

Background and purpose: Defects of coenzyme Q10 (CoQ10) metabolism cause a variety of disorders ranging from isolated myopathy to multisystem involvement. ADCK3 is one of several genes associated with CoQ10 deficiency that presents with progressive cerebellar ataxia, epilepsy, migraine and psychiatric disorders. Diagnosis is challenging due to the wide clinical spectrum and overlap with other mitochondrial disorders. Methods: A detailed description of three new patients and one previously reported patient from three Norwegian families with novel and known ADCK3 mutations is provided focusing on the epileptic semiology and response to treatment. Mutations were identified by whole exome sequencing and in two measurement of skeletal muscle CoQ10 was performed. Results: All four patients presented with childhood-onset epilepsy and progressive cerebellar ataxia. Three patients had epilepsia partialis continua and stroke-like episodes affecting the posterior brain. Electroencephalography showed focal epileptic activity in the occipital and temporal lobes. Genetic investigation revealed ADCK3 mutations in all patients including a novel change in exon 15: c.T1732G, p.F578V. There was no apparent genotype−phenotype correlation. Conclusion: ADCK3 mutations can cause a combination of progressive ataxia and acute epileptic encephalopathy with stroke-like episodes. The clinical, radiological and electrophysiological features of this disorder mimic the phenotype of polymerase gamma (POLG) related encephalopathy and it is therefore suggested that ADCK3 mutations be considered in the differential diagnosis of mitochondrial encephalopathy with POLG-like features

MRI of the index patient at the age of 54 years.

<p>A. Sagital T1 weighted MRI of the brain showing atrophy of the cerebellar midline, particularly the vermis superior. B&C. Axial T2 weighted MRI showing linear T2 hypointensities in the pons. C. Axial T2 weighted MRI showing prolongation of T2 signal in the dentate nuclei. D. Sagital T2 weighted MRI showing atrophy of the cord, straight dorsal spine and loss of the dorsal kyphosis.</p

Compound heterozygous mutations found in the proband.

<p>Upper part, IGV-browser screenshots of the mutations found by exome sequencing and corresponding Sanger sequencing results. Lower part. Protein multiple sequence alignments (PMSA) of the corresponding residues generated by MUSCLE v3.6 (NCBI HomoloGene) including genes conserved in bony vertebrates (Euteleostomi). Residues in red are predicted to be affected by the mutations found in the proband.</p