PP05.11 – 3025: A new syndrome with postnatal microcephaly, mental retardation, spastic quadriplegia and pontocerebellar atrophy in Caucasus-Jewish families (original) (raw)
Frontiers in Neurology, 2023
Biallelic loss-of-function variants in MED cause a recessive syndromic intellectual disability condition with or without epilepsy (MRT). Due to the small number of reported individuals, the clinical phenotype of the disorder has not been fully delineated yet, and the spectrum and frequency of neurologic features have not been fully characterized. Here, we report a-year-old girl with compound heterozygous for two additional MED variants. Besides global developmental delay, axial hypotonia and peripheral increased muscular tone, absent speech, and generalized tonic seizures, which fit well MRT , the occurrence of postnatal progressive microcephaly has been here documented. A retrospective assessment of the previously reported clinical data for these subjects confirms the occurrence of postnatal progressive microcephaly as a previously unappreciated feature of the phenotype of MED-related disorder.
Comprehensive review on the molecular genetics of autosomal recessive primary microcephaly (MCPH)
Genetics Research
Primary microcephaly (MCPH) is an autosomal recessive sporadic neurodevelopmental ailment with a trivial head size characteristic that is below 3–4 standard deviations. MCPH is the smaller upshot of an architecturally normal brain; a significant decrease in size is seen in the cerebral cortex. At birth MCPH presents with non-progressive mental retardation, while secondary microcephaly (onset after birth) presents with and without other syndromic features. MCPH is a neurogenic mitotic syndrome nevertheless pretentious patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Eighteen MCPH loci (MCPH1–MCPH18) have been mapped to date from various populations around the world and contain the following genes: Microcephalin, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6, MFSD2A, ANKLE2, CIT and WDFY3, clarifying our understanding about the molecular basis of microcephaly genetic disorder. It has previously been r...
Frontiers in Genetics, 2018
Chromosome 17p13.3 is a region of genomic instability that is linked to different rare neurodevelopmental genetic diseases, depending on whether a deletion or duplication of the region has occurred. Chromosome microdeletions within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). Both conditions are associated with a smooth cerebral cortex, or lissencephaly, which leads to developmental delay, intellectual disability, and seizures. However, patients with MDS have larger deletions than patients with ILS, resulting in additional symptoms such as poor muscle tone, congenital anomalies, abnormal spasticity, and craniofacial dysmorphisms. In contrast to microdeletions in 17p13.3, recent studies have attracted considerable attention to a condition known as a 17p13.3 microduplication syndrome. Depending on the genes involved in their microduplication, patients with 17p13.3 microduplication syndrome may be categorized into either class I or class II. Individuals in class I have microduplications of the YWHAE gene encoding 14-3-3ε, as well as other genes in the region. However, the PAFAH1B1 gene encoding LIS1 is never duplicated in these patients. Class I microduplications generally result in learning disabilities, autism, and developmental delays, among other disorders. Individuals in class II always have microduplications of the PAFAH1B1 gene, which may include YWHAE and other genetic microduplications. Class II microduplications generally result in smaller body size, developmental delays, microcephaly, and other brain malformations. Here, we review the phenotypes associated with copy number variations (CNVs) of chromosome 17p13.3 and detail their developmental connection to particular microdeletions or microduplications. We also focus on existing single and double knockout mouse models that have been used to study human phenotypes, since the highly limited number of patients makes a study of these conditions difficult in humans. These models are also crucial for the study of brain development at a mechanistic level since this cannot be accomplished in humans. Finally, we emphasize the usefulness of the CRISPR/Cas9 system and next generation sequencing in the study of neurodevelopmental diseases.
Research Square (Research Square), 2023
Neurodegenerative disorders (NDs) are rare multifactorial disorders characterized by dysfunction and degeneration of synapses, neurons, and glial cells which are essential for movement, coordination, muscle strength, sensation and cognition. It may also be associated with neuroin ammation and oxidative stress. Several genes have been identi ed underlying the different forms. Herein, we describe seven patients from 6 Egyptian families. The core clinical features of our patients included dysmorphic features, neurodevelopmental delay or regression, gait abnormalities, skeletal deformities, visual impairment, and seizures. Previously unreported clinical phenotypic ndings were recorded. Whole-exome sequencing (WES) was performed followed by in silico analysis of the detected genetic variants effect on the protein structure. Three novel variants were identi ed in three genes "MFSD8 (CLN7), AGTPBP1, and APTX" and other previously reported three variants have been detected in "TPP1, AGTPBP1 and PCDHGC4" genes. In this cohort, we described the detailed unique phenotypic characteristics in view of the identi ed genetic pro le in patients with ND disorders, hence expanding the mutational spectrum of such disorders. On the clinical level, NDs share similar manifestations including visual and hearing impairment, seizures, skeletal deformities, feeding and intellectual di culties [3]. Therefore, reaching a speci c diagnosis could be quite challenging in the pediatric age group especially in resource-limited countries due to several reasons such as "the ability of the clinicians to discriminate between the loss of a previously acquired or a delay in the achievement of speci c developmental milestones, lack of expertise and the long list of unaffordable potential investigations including molecular genetic analysis [4]. On the molecular and biochemical level, NDs are characterized by depositions of misfolded, toxic conformations of various proteins, which generally accumulate to form insoluble deposits [5]. Neuronal ceroid lipofuscinosis (NCLs) are a group of clinically and genetically heterogeneous ND lysosomal storage disorders that mostly present by seizures, visual impairment, and a progressive decline in cognitive and motor abilities due to progressive neuronal death [6]. Lysosomal accumulation of auto uorescent lipopigments and proteins in the central nervous system is a key pathological nding of NCLs [7]. This storage process is associated with selective destruction and loss of neurons in brain and retina. Prior to the revolution in the genetic science, the NCLs classi cation was based on the age of onset and the ultrastructural electron microscopic ndings [7]. Currently, the NCL family includes 14 different subtypes, each having distinct monogenetic defects in genes encoding proteins in the endolysosomal system. The global combined incidence of NCL is estimated to be 1:12,500 to 1: 100,000 [8]. All encountered genes lie on autosomes and in most cases, the disease is inherited in a recessive manner, with the exception of adult onset NCL caused by dominantly inherited mutations in CLN4/DNAJC5. Some NCL genes encode lysosomal proteins-enzymes and soluble proteins such as (CLN1/PPT1, CLN2/TPP1, CLN5, CLN10/CTSD, CLN13/CTSF, CLN11/GRN,) or membrane proteins (CLN3, CLN7/MFSD8, CLN12/ATP13A2). Two encode endoplasmic reticulum membrane proteins (CLN6, CLN8), while other NCL proteins are cytoplasmic (CLN4/DNAJC5, CLN14/KCTD7) that peripherally associate with cellular membranes [9, 10]. Nowadays, the early identi cation of the molecular NCLs type became very crucial in view of the novel therapeutic approaches for the NCLs and lysosomal storage disorders (LSDs) [11]. Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA; OMIM # 618276) is a rare autosomal recessive (AR) NDs that is caused by variants in the AGTPBP1 gene. AGTPBP1 gene (OMIM *606830) is located on chromosome 9 and encodes cytosolic carboxypeptidase 1 (CCP1), an enzyme involved in deglutamylation of polyglutamylated proteins [12, 13]. All patients with CONDCA had a progressive disease course and presented with impaired intellectual development, poor or absent speech and motor abnormalities. Additional features included microcephaly, strabismus, nystagmus, muscle weakness and atrophy, ataxia, spasticity, tongue fasciculation, and axonal motor neuropathy [14]. Ataxia-ocular apraxia type 1 (AOA1), another NDs was associated with mutations in APTX gene and it is the only gene known to be associated with it. AOA1 patients commonly present with cerebellar ataxia with peripheral axonal neuropathy, limitation of ocular movements on command, and hypoalbuminemia. APTX gene encodes aprataxin protein that is involved in the repair of DNA damage in cells of various tissues, including the brain, spinal cord, and muscles through its nucleotide-binding activity and its diadenosine polyphosphate hydrolase activity [15]. Neurodevelopmental disorder with poor growth and skeletal anomalies (NEDGS) (OMIM; 619880) is a global NDs with highly variable features characterized by progressive microcephaly, short stature, intellectual disability, seizures, developmental delay and joint anomalies. Mutations in the PCDHGC4 gene were identi ed in the affected individuals by Iqba et al in 2021 [16]. In this study, we will review the clinical features, explore the molecular and mutation spectrum in seven Egyptian patients with NDs with an overlapping phenotype. We employed whole exome sequencing (WES) to screen the mutations and investigate the genotypic and phenotypic heterogeneities of molecularly characterized patients. By this, we aim to provide a better understanding of NDs among clinicians especially in resource-limited countries to help them offer appropriate management, prognosis expectations and proper genetic counseling.
Neuromuscular Disorders, 2019
S201 symptoms of motor and sensory neuropathy in childhood or early adulthood with additional features like intellectual disability, cranial nerve involvement and seizures. In addition to the MORC2 hotspot mutation p.R190W, several familial mutations have been described. A distinct infantile-onset phenotype due to de novo MORC2 mutations has been described so far in six CMT2Z patients. These patients share a spinal muscular atrophy (SMA)-like phenotype with concomitant sensory and developmental abnormalities and, in some cases, respiratory distress. They harbor either the p.S25L or p.T362R mutation. The latter mutation is also associated with cerebellar atrophy. We report on two girls from unrelated families, born to non-consanguineous, healthy parents of Bangladeshi (pt1) and Austrian (pt2) origin, respectively. Both patients became symptomatic at age 6 months with muscle hypotonia, weakness and areflexia. They developed a SMA-like phenotype, showed denervation symptoms, learned to sit independently, but did not learn to get into the sitting or standing position without support (last follow up at 55 and 66 months, respectively). In pt2, progressive signs of a peripheral neuropathy and weakness of respiratory muscles were evident. Global development was delayed in both patients. Electroneurography demonstrated a primary axonal (pt1) and intermediate (pt2) polyneuropathy. Brain MRI was normal in pt1, but showed cerebellar atrophy in pt2. Pt1 carries the MORC2 mutation p.S25L (pt1), pt2 the p.T362R mutation. Our patients add evidence, that the mutations p.S25L and p.T362R are pathogenic and associated with an infantile-onset CMT2Z phenotype. This condition is an important differential diagnosis of 5q SMA, especially when sensory involvement, developmental delay, respiratory muscle weakness and cerebellar atrophy are present.