Introduction: SMG9 deficiency is an extremely rare autosomal recessive condition originally described in three patients from two families harboring homozygous truncating SMG9 variants in a context of severe syndromic developmental disorder.To our knowledge, no additional patient has been described since this first report. Methods:We performed exome sequencing in a patient exhibiting a syndromic developmental delay and in her unaffected parents and report the phenotypic features.Results: Our patient presented with a syndromic association of severe global developmental delay and diverse malformations, including cleft lip and palate, facial dysmorphic features, brain abnormalities, heart defect, growth retardation, and severe infections. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous. Conclusions:We confirm that bi-allelic truncating SMG9 variants cause a severe developmental syndrome including brain and heart malformations associated with facial dysmorphic features, severe growth and developmental delay with or without ophthalmological abnormalities, severe feeding difficulties, and life-threatening infections. K E Y W O R D Sheart and brain malformation, nonsense mediated decay, SMG9
3-Hydroxy 3-Methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease.
Background Duplication of the 17q21.3 region, leading to increased MAPT expression, causes a rare atypical early‐onset dementia (EOD) mimicking Alzheimer’s Disease (AD) clinical presentation. Since our initial report in 2016, the same duplication has been identified in additional patients including 2 progressive supranuclear palsy (PSP) patients. It remains unclear whether MAPT duplication‐associated phenotypes are purely cognitive and if clinical and neuroimaging data are suggestive of a pure tauopathy or an amyloid plus tau underlying pathology. Method We report in this study clinical and paraclinical data from 10 MAPT duplication carriers, including 8 with a clinical EOD presentation and two recently identified during the screening of a series of PSP cases. All clinical data were collected as well as family history, neuropsychological assessment, 3D‐structural MRI (n = 7 patients), fluorodesoxyglucose‐PET (n = 5), DaTSCAN SPECT (n = 2), Amyloid‐PET (n = 3) and Tau‐PET (n = 2). Six patients had AD cerebrospinal fluid (CSF) biomarkers measured. Results were interpreted following Amyloid/Tau/Neurodegeneration (A/T/N) classification. Result Among the 10 patients, 6 had a positive family history of EOD, with cosegregation in one family. In one of the 4 sporadic patients, we could demonstrate that the duplication occurred de novo. Mean age of onset was 50.4 years [37‐58]. Eight presented a pure cognitive decline with an initial episodic amnesic syndrome. A behavioral dysexecutive syndrome was found in 5 patients (50%). Two patients were diagnosed as PSP but no or minor extrapyramidal signs were found among the 8 cognitive patients, despite 2 DaTSCANS showing presynaptic dopaminergic denervation. MRI of 6 cases (86%) showed hippocampal and temporoparietal bilateral atrophy. All CSF biomarkers were T+ and N+. Amyloid CSF biomarkers were abnormal in 3/6, suggestive of A+, however all three had negative amyloid‐PET. Interestingly, both Tau‐PET imaging showed strong deposits of Tau pathology within mesiotemporal regions and mild frontal cortex uptake in one patient (Figure). The neuropathology of two patients is currently being examined and will be presented. Conclusion This largest series of MAPT duplications carriers shows a heterogeneous expression with clinical and neuroimaging data suggesting mixed cortical and subcortical impairment with diverse clinical consequences. We will confront these data to the results of the neuropathological examinations.
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