BackgroundHuntington's disease (HD) is a fatal inherited neurodegenerative disease, caused by a

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BackgroundHearing loss and ovarian dysfunction are key features of Perrault syndrome (PRLTS) but the clinical and pathophysiological features of hearing impairment in PRLTS individuals have not been addressed. Mutations in one of five different genes HSD17B4, HARS2, LARS2, CLPP or TWNK (previous symbol C10orf2) cause the autosomal recessive disorder but they are found only in about half of the patients.MethodsWe report on two siblings with a clinical picture resembling a severe, neurological type of PRLTS. For an exhaustive characterisation of the phenotype neuroimaging with volumetric measurements and objective measures of cochlear hair cell and auditory nerve function (otoacustic emissions and auditory brainstem responses) were used. Whole exome sequencing was applied to identify the genetic cause of the disorder. Co-segregation of the detected mutations with the phenotype was confirmed by Sanger sequencing. In silico analysis including 3D protein structure modelling was used to predict the deleterious effects of the detected variants on protein function.ResultsWe found two rare biallelic mutations in TWNK, encoding Twinkle, an essential mitochondrial helicase. Mutation c.1196A>G (p.Asn399Ser) recurred for the first time in a patient with PRLTS and the second mutation c.1802G>A (p.Arg601Gln) was novel for the disorder. In both patients neuroimaging studies showed diminished cervical enlargement of the spinal cord and for the first time in PRLTS partial atrophy of the vestibulocochlear nerves and decreased grey and increased white matter volumes of the cerebellum. Morphological changes in the auditory nerves, their desynchronized activity and partial cochlear dysfunction underlay the complex mechanism of hearing impairment in the patients.ConclusionsOur study unveils novel features on the phenotypic landscape of PRLTS and provides further evidence that the newly identified for PRLTS TWNK gene is involved in its pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1129-4) contains supplementary material, which is available to authorized users.

PIGT is one of over 29 glycosylphosphatidylinositol biosynthesis defect genes. Mutations cause genetically determined disorders characterized mainly by epilepsy with fever-sensitivity, central hypotonia, psychomotor delay and congenital malformations. The disease is known as multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) or glycosylphosphatidylinositol biosynthesis defect-7. Twenty-eight cases have been reported until today. We present seven novel Polish patients, all harboring 1582G>A variant in a homozygous or compound heterozygous state which seems to cause a milder phenotype of the disease. K E Y W O R D S antiepileptic drugs, developmental encephalopathy with epilepsy, fever-associated epilepsy, glycosylphosphatidylinositol biosynthesis defects, PIGT gene 1 | INTRODUCTION Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) are an emerging group of genetically determined disorders caused by a pathogenic variant of over 29 genes. 1,2 The first cases were described by Mabry et al in 1970 as familial cases of developmental delay (DD) and seizures with elevated serum alkaline phosphatase (ALP) concentration. 3,4 The majority of these disorders are characterized by intractable seizures, which occur during the neonatal period or infancy and are proceeded by hypotonia and psychomotor delay. Congenital malformations were also described in the literature. 2 These included diaphragmatic hernias in patients with PIGN-GPIBD variants and megacolon in patients with PIGV, PIGO and PGAP2 mutations. 1 Mutations in the PIGT gene were first described by Kvarnung et al in 2013. 5 The resulting syndrome, PIGT-GPIBD, is also known as multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) or GPIBD7 (MIM 615398). Since 2013, 28 cases have been reported, 6,7 while the largest cohort was reviewed by Bayat et al. 6 Patients Jezela-Stanek Aleksandra, Szczepanik Elżbieta and Mierzewska Hanna contributed equally to this work.

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