ABSTRACT
Perrault syndrome (PS) is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. Recently, mutations in five genes have been identified: C10orf2, CLPP, HARS2, ...HSD17B4, and LARS2. Probands included are presented with sensorineural deafness associated with gonadic dysgenesis. DNA was sequenced using next‐generation sequencing (NGS) with a panel of 35 deafness genes including the five Perrault genes. Exonic variations known as pathogenic mutations or detected with <1% frequency in public databases were extracted and subjected to segregation analysis within each family. Both mutations and low coverage regions were analyzed by Sanger sequencing. Fourteen female index patients were included. The screening in four cases has been extended to four family members presenting with PS phenotype. For four unrelated patients (28.6%), causative mutations were identified: three homozygous mutations in C10orf2, CLPP, and HARS2, and one compound heterozygous mutation in LARS2. Three additional heterozygous mutations in LARS2 and HSD17B4 were found in three independent familial cases. All these missense mutations were verified by Sanger sequencing. Familial segregation analyses confirmed the molecular diagnosis in all cases carrying biallelic mutations. Because of NGS, molecular analysis confirmed the clinical diagnosis of PS in 28.6% of our cohort and four novel mutations were found in four Perrault genes. For the unsolved cases, exome sequencing should be performed to search for a sixth unknown PS gene.
Perrault syndrome is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. In the literature 98 cases have been reported and only 25 mutations in the five Perrault genes have been identified. Thanks to NGS, four novel mutations have been identified in four Perrault genes (C10orf2, CLPP, HARS2 and LARS2). Molecular analysis confirmed the clinical diagnosis in 28.6% and some genotype‐phenotype correlations were established.
Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually ...increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5′ of the CTG expansion in one family, whereas multiple 5′ CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet‐prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3′ of the interruptions for both families.
Myotonic dystrophy type 1 is a dominant multisystemic disorder caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. We described an unique CAG interruption or multiple CCG interruptions in the 5' end of the CTG repeat tract in two atypical DM1 families. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood.
Pathogenic GFM1 variants have been linked to neurological phenotypes with or without liver involvement, but only a few cases have been reported in the literature.
Here, we report clinical, ...biochemical, and neuroimaging findings from nine unrelated children carrying GFM1 variants, 10 of which were not previously reported. All patients presented with neurological involvement—mainly axial hypotonia and dystonia during the neonatal period—with five diagnosed with West syndrome; two children had liver involvement with cytolysis episodes or hepatic failure. While two patients died in infancy, six exhibited a stable clinical course. Brain magnetic resonance imaging showed the involvement of basal ganglia, brainstem, and periventricular white matter. Mutant EFG1 and OXPHOS proteins were decreased in patient's fibroblasts consistent with impaired mitochondrial translation. Thus, we expand the genetic spectrum of GFM1‐linked disease and provide detailed clinical profiles of the patients that will improve the diagnostic success for other patients carrying GFM1 mutations.
OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X‐linked OTC gene. Phenotype‐genotype correlations are well understood in males but still poorly known in females. ...Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation, and OTC gene sequencing to genetic counseling in heterozygous females. Twenty two percent of the heterozygous females were clinically affected, with episodic (11%), chronic (7.5%), or neonatal forms of the disease (3.5%). Overall mortality rate was 4%. OTC activity, ranging from 0% to 60%, did not correlate with phenotype at the individual level. Analysis of multiple samples from 4 mutant livers showed intra‐hepatic variability of OTC activity and X inactivation profile (range of variability: 30% and 20%, respectively) without correlation between both parameters for 3 of the 4 livers. Ninety disease‐causing variants were found, 27 of which were novel. Mutations were classified as “mild” or “severe,” based on male phenotypes and/or in silico prediction. In our cohort, a serious disease occurred in 32% of females with a severe mutation, compared to 4% in females with a mild mutation (odds ratio = 1.365; P = 1.6e‐06). These data should help prenatal diagnosis for heterozygous females and genetic counseling after fortuitous findings of OTC variants in pangenomic sequencing.
Objective
To report an adolescent with infantile‐onset carnitine palmitoyltransferase 2 (CPT2) deficiency and cerebral malformations and to review the occurrence of brain malformations in CPT2 ...deficiency. The patient presented clinically at age 5 months with dehydration and hepatomegaly. He also has an unrelated condition, X‐linked nephrogenic diabetes insipidus. He had recurrent rhabdomyolysis but normal psychomotor development. At age 17 years, he developed spontaneous focal seizures. Cerebral magnetic resonance imaging revealed extensive left temporo‐parieto‐occipital polymicrogyria, white matter heterotopias, and schizencephaly. Neuronal migration defects were previously reported in lethal neonatal CPT2 deficiency but not in later‐onset forms.
Design and Methods
We searched PubMed, Google Scholar, and the bibliographies of the articles found by these searches, for cerebral malformations in CPT2 deficiency. All antenatal, neonatal, infantile, and adult‐onset cases were included. Exclusion criteria included insufficient information about age of clinical onset and lack of confirmation of CPT2 deficiency by enzymatic assay or genetic testing. For each report, we noted the presence of cerebral malformations on brain imaging or pathological examination.
Results
Of 26 neonatal‐onset CPT2‐deficient patients who met the inclusion criteria, brain malformations were reported in 16 (61.5%). In 19 infantile‐onset cases, brain malformations were not reported, but only 3 of the 19 reports (15.8%) include brain imaging or neuropathology data. In 276 adult‐onset cases, no brain malformations were reported.
Conclusion
To the best of our knowledge, this is the first report of cerebral malformations in an infantile onset CPT2‐deficient patient. Brain imaging should be considered in patients with CPTII deficiency and neurological manifestations, even in those with later clinical onset.
Propionic acidemia is the result of a deficiency in propionyl-CoA carboxylase activity. Chronic neurologic and cognitive complications frequently occur, but the psychiatric evolution of the disorder ...is not well documented. We conducted a pedopsychiatric evaluation of 19 children, adolescents and young adults, aged between 2 and 25 years, using ADI-R, CARS-T, as well as ADOS when autism spectrum disorder was suspected. Previous psychometric examinations were also taken into consideration. Thirteen patients had an IQ < 80. Two patients presented with autism and two additional patients with other autism spectrum disorders. Five patients did not fulfill diagnostic criteria for autism spectrum disorder but showed difficulties indicative of a broader autism phenotype (BAP). Four other patients had severe anxiety manifestations related to their disease. Two patients presented with acute psychotic episodes. The number of decompensations in the first 3 years of life was lower in patients with autism spectrum disorder or related symptoms. These patients were also older when they were assessed (median age of 15 years old versus 11 years old). There was no significant correlation between 3-hydroxypropionate levels during the first 6 years of life and autism spectrum disorder diagnosis. In conclusion, autism spectrum disorder is frequent in patients with propionic acidemia. These patients should undergo in-depth psychiatric evaluation and be screened for autism spectrum disorder. Further studies are needed to understand the underlying mechanisms.
Carnitine palmitoyltransferase (CPT) deficiencies are common disorders of mitochondrial fatty acid oxidation. The CPT system is made up of two separate proteins located in the outer (CPT1) and inner ...(CPT2) mitochondrial membranes. While CPT2 is an ubiquitous protein, three tissue-specific CPT1 isoforms––the so-called “liver” (CPT1-A), “muscle” (CPT1B) and
«brain» (CPT1-C) CPT1s––have been shown to exist. Amino acid and cDNA nucleotide sequences have been identified for all of these proteins. CPT1-A deficiency presents as recurrent attacks of fasting hypoketotic hypoglycemia. Twenty four
CPT1A mutations have been reported to date. CPT1-B and -C deficiencies have not been hitherto identified. CPT2 deficiency has several clinical presentations. The “benign” adult form (more than 200 families reported) is characterized by episodes of rhabdomyolysis triggered by prolonged exercise. The prevalent S113L mutation is found in about 50% of mutant alleles. The infantile-type CPT2 presents as severe attacks of hypoketotic hypoglycemia, occasionally associated with cardiac damage commonly responsible for sudden death before 1 year of age. In addition to these symptoms, features of brain and kidney dysorganogenesis are frequently seen in the neonatal-onset CPT2 deficiency, almost always lethal during the first month of life. Around 40 CPT2 mutations (private missense or truncating mutations) have hitherto been detected. Treatment is based upon avoidance of fasting and/or exercise, a low fat diet enriched with medium chain triglycerides and carnitine. Prenatal diagnosis may be offered for pregnancies at a 1/4 risk of infantile/severe-type CPT2 deficiency.
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