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IntroductionThis study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB).MethodsClinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.ResultsThe clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.ConclusionThis study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.

Le Professeur Thierry Frébourg est décédé brutalement le 13 mars 2021 à l’âge de 60 ans. Ses collègues et amis généticiens de la Filière FILNEMUS lui rendent hommage, lui qui a tant fait pour les maladies rares.

The detection of copy-number variations (CNVs) from NGS data is underexploited as chip-based or targeted techniques are still commonly used. We assessed the performances of a workflow centered on CANOES, a bioinformatics tool based on read depth information. We applied our workflow to gene panel (GP) and whole-exome sequencing (WES) data, and compared CNV calls to quantitative multiplex PCR of short fluorescent fragments (QMSPF) or array comparative genomic hybridization (aCGH) results. From GP data of 3776 samples, we reached an overall positive predictive value (PPV) of 87.8%. This dataset included a complete comprehensive QMPSF comparison of four genes (60 exons) on which we obtained 100% sensitivity and specificity. From WES data, we first compared 137 samples with aCGH and filtered comparable events (exonic CNVs encompassing enough aCGH probes) and obtained an 87.25% sensitivity. The overall PPV was 86.4% following the targeted confirmation of candidate CNVs from 1056 additional WES. In addition, our CANOES-centered workflow on WES data allowed the detection of CNVs with a resolution of single exons, allowing the detection of CNVs that were missed by aCGH. Overall, switching to an NGS-only approach should be cost-effective as it allows a reduction in overall costs together with likely stable diagnostic yields. Our bioinformatics pipeline is available at: https://gitlab.bioinfo-diag.fr/nc4gpm/canoes-centered-workflow.

Background:Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1gene. The SMN2copy number modulates the severity of SMA. The 0SMN1/1SMN2genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. Objective:The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. Methods:SMA patients with the 0SMN1/1SMN2genotype were retrospectively collected using the UMD-SMN1 France database. Results:Data from 16 patients were reviewed. These 16 patients displayed type 0 SMA. At birth, a vast majority had profound hypotonia, severe muscle weakness, severe respiratory distress, and cranial nerves involvement (inability to suck/swallow, facial muscles weakness). They showed characteristics of fetal akinesia deformation sequence and congenital heart defects. Recurrent episodes of bradycardia were observed. Death occurred within the first month. At prenatal stage, decreased fetal movements were frequently reported, mostly only by mothers, in late stages of pregnancy; increased nuchal translucency was reported in about half of the cases; congenital heart defects, abnormal amniotic fluid volume, or joint contractures were occasionally reported. Conclusion:Despite a prenatal onset attested by severity at birth and signs of fetal akinesia deformation sequence, prenatal manifestations of type 0 SMA are not specific and not constant. As illustrated by the frequent association with congenital heart defects, type 0 SMA physiopathology is not restricted to motor neuron, highlighting that SMN function is critical for organogenesis.

Semaphorins are a large family of secreted and membrane-associated proteins necessary for wiring of the brain. Semaphorin 5A (SEMA5A) acts as a bifunctional guidance cue, exerting both attractive and inhibitory effects on developing axons. Previous studies have suggested that SEMA5Acould be a susceptibility gene for autism spectrum disorders (ASDs). We first identified a de novotranslocation t(5;22)(p15.3;q11.21) in a patient with ASD and intellectual disability (ID). At the translocation breakpoint on chromosome 5, we observed a 861-kb deletion encompassing the end of the SEMA5Agene. We delineated the breakpoint by NGS and observed that no gene was disrupted on chromosome 22. We then used Sanger sequencing to search for deleterious variants affecting SEMA5Ain 142 patients with ASD. We also identified two independent heterozygous variants located in a conserved functional domain of the protein. Both variants were maternally inherited and predicted as deleterious. Our genetic screens identified the first case of a de novo SEMA5Amicrodeletion in a patient with ASD and ID. Although our study alone cannot formally associate SEMA5Awith susceptibility to ASD, it provides additional evidence that Semaphorin dysfunction could lead to ASD and ID. Further studies on Semaphorins are warranted to better understand the role of this family of genes in susceptibility to neurodevelopmental disorders.

The increasing use of array-CGH in malformation syndromes with intellectual disability could lead to the description of new contiguous gene syndrome by the analysis of the gene content of the microdeletion and reverse phenotyping. Thanks to a national and international call for collaboration by Achropuce and Decipher, we recruited four patients carrying de novooverlapping deletions of chromosome 9q33.3q34.11, including the STXBP1, the LMX1Band the ENGgenes. We restrained the selection to these three genes because the effects of their haploinsufficency are well described in the literature and easily recognizable clinically. All deletions were detected by array-CGH and confirmed by FISH. The patients display common clinical features, including intellectual disability with epilepsy, owing to the presence of STXBP1within the deletion, nail dysplasia and bone malformations, in particular patellar abnormalities attributed to LMX1Bdeletion, epistaxis and cutaneous–mucous telangiectasias explained by ENGhaploinsufficiency and common facial dysmorphism. This systematic analysis of the genes comprised in the deletion allowed us to identify genes whose haploinsufficiency is expected to lead to disease manifestations and complications that require personalized follow-up, in particular for renal, eye, ear, vascular and neurological manifestations.

BACKGROUND Episodic ataxia (EA) is an ion channel disorder that manifests as paroxysmal attacks of imbalance and incoordination. Episodic ataxia type 2 (EA2) is characterized by prolonged episodes of ataxia with interictal nystagmus and is caused by mutations in CACNA1A. All mutations identified thus far (to our knowledge) are nonsense or missense point mutations. OBJECTIVE To describe a family with EA2 having a novel mutation deleting several exons of CACNA1A. DESIGN Clinical and molecular study of a family manifesting EA2 attacks. SETTING Academic research. PATIENTS DNA was extracted from blood samples of 3 family members. MAIN OUTCOME MEASURES Microsatellite genotyping of CACNA1A, quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF), and sequencing were performed. RESULTS Genotyping of CACNA1A showed nonmendelian inheritance of a CAG repeat located at the 3′ end of the gene in a mother and daughter, suggesting a deletion event, which was subsequently confirmed by QMPSF analysis and sequencing. This 39.5-kilobase deletion removes the last 16 coding exons of the gene. CONCLUSION Deletion of several exons of CACNA1A may cause EA2 and should be assessed in patients having EA2 without a CACNA1A point mutation.Arch Neurol. 2008;65(6):817-820--

Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons and caused by mutations of the SMN1gene. SMN1is duplicated in a homologous gene called SMN2, which remains present in patients. SMN has an essential role in RNA metabolism, but its role in SMA pathogenesis remains unknown. Previous studies suggested that in neurons the protein lacking the C terminus (SMNΔ7), the major product of the SMN2gene, had a dominant-negative effect. We generated antibodies specific to SMNFLor SMNΔ7. In transfected cells, the stability of the SMNΔ7protein was regulated in a cell-dependent manner. Importantly, whatever the human tissues examined, SMNΔ7protein was undetectable because of the instability of the protein, thus excluding a dominant effect of SMNΔ7in SMA. A similar decreased level of SMNFLwas observed in brain and spinal cord samples from human SMA, suggesting that SMNFLmay have specific targets in motor neurons. Moreover, these data indicate that the vulnerability of motor neurons cannot simply be ascribed to the differential expression or a more dramatic reduction of SMNFLin spinal cord when compared with brain tissue. Improving the stability of SMNΔ7protein might be envisaged as a new therapeutic strategy in SMA.

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Holt–Oram syndrome, the major “heart–hand” syndrome is defined by the association of radial defects or triphalangeal thumbs and septal heart defects. The transmission is autosomal dominant and the causative gene has been shown to be TBX5, located on 12q24.1, which encodes a transcription factor. Genetic heterogeneity has been suggested by several reports. We identified a 14(q23.3 ∼ 24.2q31.1) deletion in a boy presenting severe bilateral asymmetrical radial aplasia, congenital heart defects, and developmental delay. This deletion, whose size could be estimated to be 9.6–13.7 Mb, was shown to be inherited via his mother's interchromosomal insertion. This is the second report of a chromosome 14 interstitial deletion associated with clinical features of Holt–Oram syndrome. These observations suggest the existence of a new “heart–hand” locus on chromosome 14q. © 2005 Wiley‐Liss, Inc.

The majority of proximal myotonic myopathy syndromes reported so far have been related to the myotonic dystrophy (DM) type 2 (DM2) mutation, an expanded (CCTG)n repeat in the ZNF9 gene. Here, we describe the phenotype and the histological features in muscle and brain of the first large pedigree with a non-myotonic dystrophy type 1 (DM1) non-DM2 multisystem myotonic disorder associated with severe frontotemporal dementia. Thirty individuals from three generations underwent detailed neurological, neuropsychological, electrophysiological, brain imaging and molecular analyses. Ten of them had proximal muscle weakness at onset, clinical/electrical myotonia and DM-type cataracts. The mean age at onset was 46.7 ± 12.6 years (range: 32–69). Dementia was observed later in the course of the disease. On muscle biopsies, rare nuclear clumps, rimmed vacuoles and small angulated type 1 and type 2 fibres were seen early in the disease. They were replaced by fibrous adipose tissue at later stages. Immunohistochemical analysis of myosin heavy chain isoforms showed no selective fibre type atrophy—both type 1 and type 2 fibres being affected. Cortical atrophy without white matter lesions was seen on brain MRI. A brain single photon emission computed tomography (SPECT) study revealed marked frontotemporal hypoperfusion. Post-mortem examination of the brains of two patients showing prominent frontotemporal spongiosis, neuronal loss and rare neuronal and glial tau inclusions suggested frontotemporal dementia. Western blot analyses of the tau protein showed a triplet of isoforms (60, 64 and 69 kDa) in neocortical areas, and a doublet (64 and 69 kDa) in subcortical areas that distinguish our myotonic disorder from other's myotonic dystrophies. Molecular analyses failed to detect a repeat expansion in the DMPK and ZNF9 genes excluding both DM1 and DM2, whereas a genome-wide linkage analysis strongly suggested a linkage to chromosome 15q21-24. This previously unreported multisystem myotonic disorder including findings resembling DM1, DM2 and frontotemporal dementia provides further evidence of the clinical and genetic heterogeneity of the myotonic dystrophies. We propose to designate this disease myotonic dystrophy type 3, DM3.

X‐linked lissencephaly with absent corpus callosum and ambiguous genitalia is a newly recognized syndrome responsible for a severe neurological disorder of neonatal onset in boys. Based on the observations of 3 new cases, we confirm the phenotype in affected boys, describe additional MRI findings, report the neuropathological data, and show that carrier females may exhibit neurological and magnetic resonance imaging abnormalities. In affected boys, consistent clinical features of X‐linked lissencephaly with absent corpus callosum and ambiguous genitalia are intractable epilepsy of neonatal onset, severe hypotonia, poor responsiveness, genital abnormalities, and early death. On magnetic resonance imaging, a gyration defect consisting of anterior pachygyria and posterior agyria with a moderately thickened brain cortex, dysplastic basal ganglia and complete agenesis of the corpus callosum are consistently found. Neuropathological examination of the brain shows a trilayered cortex containing exclusively pyramidal neurons, a neuronal migration defect, a disorganization of the basal ganglia, and gliotic and spongy white matter. Finally, females related to affected boys may have mental retardation and epilepsy, and they often display agenesis of the corpus callosum. These findings expand the phenotype of X‐linked lissencephaly with absent corpus callosum and ambiguous genitalia, may help in the detection of carrier females in affected families, and give arguments for a semidominant X‐linked mode of inheritance.

The congenital disorders of glycosylation (CDG) constitute a new group of recessively inherited metabolic disorders that are characterized biochemically by defective glycosylation of proteins. Several types have been identified. CDG-Ia, the most frequent type, is a multisystemic disorder affecting the nervous system and numerous organs including liver, kidney, heart, adipose tissue, bone, and genitalia. A phosphomannomutase (PMM) deficiency has been identified in CDG-Ia patients and numerous mutations in the PMM2 gene have been identified in patients with a PMM deficiency. We report on a French family with 3 affected sibs, with an unusual presentation of CDG-Ia, remarkable for 1) the neurological presentation of the disease, and 2) the dissociation between intermediate PMM activity in fibroblasts and a decreased PMM activity in leukocytes. This report shows that the diagnosis of CDG-Ia must be considered in patients with non-regressive early-onset encephalopathy with cerebellar atrophy, and that intermediate values of PMM activity in fibroblasts do not exclude the diagnosis of CDG-Ia. © 2001 Wiley-Liss, Inc.

Three forms of X–linked spastic paraplegia (SPG) have been defined. One locus (SPG 1) maps to Xq28 while two clinically distinct forms map to Xq22 (SPG2). A rare X–linked dysmyelinating disorder of the central nervous system, Pelizaeus–Merzbacher disease (PMD), has also been mapped to Xq21–q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20. While narrowing the genetic interval containing SPG2 in a large pedigree, we found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene. We have found that a point mutation (His139Tyr) in exon 3B of an affected male produces a mutant PLP but a normal DM20,and segregates with the disease (Zmax=6.63, θ=0.00). It appears, therefore, that SPG2 and PMD are allelic disorders.