Meriem Tazir

Homozygous Defects in LMNA, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy in Human (Charcot-Marie-Tooth Disorder Type 2) and Mouse

The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes---NF-L and KIF1Bbeta---have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Zmax=4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.

The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy

Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a β-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.

Mutations in SPG11 , encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.

ADCK3, an Ancestral Kinase, Is Mutated in a Form of Recessive Ataxia Associated with Coenzyme Q10 Deficiency

Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.

Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.

Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency

Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and antioxidant defense. The relative importance of respiratory chain defects, ROS production, and apoptosis in the pathogenesis of CoQ10 deficiency is unknown. We determined previously that severe CoQ10 deficiency in cultured skin fibroblasts harboring COQ2 and PDSS2 mutations produces divergent alterations of bioenergetics and oxidative stress. Here, to better understand the pathogenesis of CoQ10 deficiency, we have characterized the effects of varying severities of CoQ10 deficiency on ROS production and mitochondrial bioenergetics in cells harboring genetic defects of CoQ10 biosynthesis. Levels of CoQ10 seem to correlate with ROS production;10‐15% and >60% residual CoQ10 are not associated with significant ROS production, whereas 30‐50% residual CoQ10 is accompanied by increased ROS production and cell death. Our results confirm that varying degrees of CoQ10 deficiency cause variable defects of ATP synthesis and oxidative stress. These findings may lead to more rational therapeutic strategies for CoQ10 deficiency.— Quinzii, C. M., Lopez, L. C., Gilkerson, R. W., Dorado, B., Coku, J., Naini, A. B., Lagier‐Tourenne, C., Schuelke, M., Salviati, L., Carrozzo, R., Santorelli, F., Rahman, S., Tazir, M., Koenig, M., DiMauro, S., Hirano, M. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 24, 3733–3743 (2010). www.fasebj.org

The phenotypic manifestations of autosomal recessive axonalCharcot–Marie–Tooth due to a mutation in Lamin A/C gene

Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot-Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot-Marie-Tooth type 2 carrying a mutation in LMNA.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

LRRK2 G2019S mutation in Parkinson’s disease: A neuropsychological and neuropsychiatric study in a large Algerian cohort ☆

A series of 106 patients with isolated or familial Parkinsonism underwent clinical evaluation and genetic testing for the LRRK2 G2019S mutation which was identified in 34/106 patients (32%). Seventy one of them accepted to be evaluated for neuropsychological and neuropsychiatric studies with the aim to compare mutation carriers with non-carriers. For neuropsychological testing, comparisons between LRRK2 G2019S carriers and non-carriers were made after stratification according to the level of education: median and high school versus low level. Memory was investigated with the five words test, 2 novel tests with verbalized visual material dedicated to illiterate patients, the TNI-93 (nine pictures test), The TMA-93 (associative memory test), and digit spans (forward/backward). Cognitive analyse did not show major differences between the two groups of patients. Nevertheless, behavioral abnormalities, mostly depression and hallucinations, were more frequent in the LRRK2 G2019S carriers, suggesting the presence of a greater involvement of the limbic system in these patients. Sleep disorders which were also more common amongst mutation carriers than non-carriers might be related to depression.

Charcot–Marie–Tooth diseases: an update and some new proposals for the classification

Background Charcot–Marie–Tooth (CMT) disease, the most frequent form of inherited neuropathy, is a genetically heterogeneous group of disorders of the peripheral nervous system, but with a quite homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss and usually decreased tendon reflexes). Our aim was to review the various CMT subtypes identified at the present time. Methods We have analysed the medical literature and performed a historical retrospective of the main steps from the individualisation of the disease (at the end of the nineteenth century) to the recent knowledge about CMT. Results To date, >60 genes (expressed in Schwann cells and neurons) have been implicated in CMT and related syndromes. The recent advances in molecular genetic techniques (such as next-generation sequencing) are promising in CMT, but it is still useful to recognise some specific clinical or pathological signs that enable us to validate genetic results. In this review, we discuss the diagnostic approaches and the underlying molecular pathogenesis. Conclusions We suggest a modification of the current classification and explain why such a change is needed.