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To determine the genetic cause of neurodegeneration in a family with myeloneuropathy.

To study the prevalence of DEPDC5mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

To identify the genetic cause of autosomal dominant spinocerebellar ataxia type 28 (SCA28) with ptosis in 2 Belgian families without AFG3L2point mutations and further extend the clinical spectrum of SCA28 through the study of a brain autopsy, advanced MRI, and cell-based functional assays exploring the underlying disease mechanism.

To determine the genes underlying Dravet syndrome in patients who do not have an SCN1Amutation on routine testing.

To determine the frequency of KCNQ2mutations in patients with neonatal epileptic encephalopathy (NEE), and to expand the phenotypic spectrum of KCNQ2epileptic encephalopathy.

Identification of mutations in the inverted formin-2 (INF2) gene in patients with Charcot-Marie-Tooth (CMT) disease combined with focal segmental glomerulosclerosis (FSGS) in order to expand the genetic and phenotypic spectrum.

After we identified a 17q12 duplication cosegregating in a 4-generation family with genetic or generalized epilepsy with febrile seizures plus (GEFS), we aimed to determine the frequency of 17q12 genomic rearrangements in GEFS and a wide spectrum of other epilepsy phenotypes. We furthermore describe seizure prevalence in previously reported patients with a 17q12 duplication or deletion.

In this study, we investigated the detailed clinical findings and underlying genetic defect in 3 presumably related Bulgarian families displaying dominantly transmitted adult onset distal myopathy with upper limb predominance.

Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large GermanDutch pedigree has formerly been described as paroxysmal choreoathetosisspasticity (DYT9) and linked close to but not including the SLC2A1locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, in addition to PED, as described in DYT9, and 2) autosomal dominant forms of hereditary spastic paraparesis (HSP) without PED are caused by SLC2A1defects.

Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1mutations in ADCMT and their associated phenotype.

To determine the genetic etiology of the severe early infantile onset syndrome of malignant migrating partial seizures of infancy (MPSI).

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a complex neurodegenerative disorder caused by mutations in SACS. The phenotype consists of a childhood-onset triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs.

Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies.

Familial glucose transporter type 1 (GLUT1) deficiency due to autosomal dominant inheritance of SLC2A1mutations is associated with paroxysmal exertional dyskinesia; epilepsy and intellectual disability occur in some family members. We recently demonstrated that GLUT1 deficiency occurs in over 10% of patients with early-onset absence epilepsy.

The aim of this study was to determine the genetic defect in a 4-generational family with an epileptic disorder characterized by febrile and afebrile polymorphic seizures and mild to severe mental retardation by means of analyzing the neuronal voltage-gated sodium channel -subunit gene SCN1Afor mutations.

Autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy type 4H (CMT4H) manifests early onset, severe functional impairment, deforming scoliosis, and myelin outfoldings in the nerve biopsy. Mutations in the FGD4gene encoding the Rho-GTPase guanine-nucleotide-exchange-factor frabin were reported in five families.

Incidence rates of epilepsy in children are highest during the first year of life. Most frequently, epilepsy results from a metabolic or structural defect in the brain. However, some infants have clearly delineated epilepsy syndromes for which no underlying etiology can be identified except for a genetic predisposition.

To map the disease-causing locus in a large Belgian family with occipitotemporal lobe epilepsy associated with migraine with visual aura and to describe the clinical, electrophysiologic, and imaging characteristics.

To investigate the clinical and electrophysiologic phenotype of Charcot–Marie–Tooth disease (CMT) Type 2 in a large number of affected families.

Mutations in the gene encoding the γ2 subunit of the γ-aminobutyric acid type A receptor (GABRG2) have been reported to cause childhood absence epilepsy (CAE), febrile seizures (FS), and generalized epilepsy with FS plus (GEFS). The authors analyzed GABRG2in 47 unrelated patients with CAE, FS, and GEFS and identified a novel mutation that cosegregated with FS. Electrophysiologic studies demonstrated altered current desensitization and reduced benzodiazepine enhancement in mutant receptors.

Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus.

Hereditary sensory and autonomic neuropathy type II (HSAN-II) is caused by recessive mutations in the HSN2gene assigned to chromosome 12p13.33. The authors report three unrelated HSAN-II families with homozygous or compound heterozygous mutations resulting in the truncation of the HSN2 protein. Genotype–phenotype correlations indicated that HSN2mutations are associated with an early childhood onset of a predominantly sensory neuropathy, complicated by acromutilations in both upper and lower limbs.

Benign familial neonatal convulsions (BFNC) are characterized by unprovoked seizures during the first weeks of life with spontaneous remission after a few months. Mutations have been identified in the voltage-gated potassium ion channels KCNQ2 and KCNQ3. The authors performed a mutation analysis of KCNQ2and KCNQ3in six patients of whom four had no family history of neonatal seizures. The authors identified three KCNQ2mutations in four patients that all arose de novo.

To identify POLGmutations in patients with sensory ataxia and CNS features.

Charcot–Marie–Tooth disease type 2A (CMT2A) was assigned to a 19.3-cM region on chromosome 1p35–36. A missense mutation in the kinesin family member 1B gene (KIF1B) was reported in a single CMT2A family.

Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot–Marie–Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis.

Article abstract—The authors report a large pedigree from southern Italy with Charcot–Marie–Tooth disease type 2A (CMT2A). The clinical picture was uniform and characterized by distal muscular weakness and atrophy in the lower limbs, reduced or absent tendon reflexes mainly in the lower limbs, and mild sensory impairment in the feet. Significant linkage to the CMT2A locus on chromosome 1p35–p36 was detected. Based on informative recombination in affected individuals, the authors mapped the CMT2A gene between D1S160 and D1S170.

To perform genotype–phenotype correlation and genetic linkage analysis in a family with axonal Charcot-Marie-Tooth (CMT) syndrome and ulcero-mutilating features.

Mutations in the early growth response 2 (EGR2) gene have recently been found in patients with congenital hypomyelinating neuropathy and Charcot-Marie-Tooth type 1 (CMT1) disease.

A locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2A) was assigned by linkage analysis to chromosome 1p35–p36. We examined 11 unrelated CMT2 families for linkage to CMT2A using short tandem repeat (STR) polymorphisms. Only one family showed suggestive evidence for linkage to 1p35–p36. Further, because of an overlap in electrophysiologic data between CMT2 and CMTX female patients, we screened 6 of 11 CMT2 families compatible with dominant X-linkage for mutations in the connexin 32 (Cx32) gene at Xq13. There was a Cx32 mutation in one family, whereas another family showed suggestive evidence for Xq13 linkage upon analysis with STR polymorphisms. Our results suggest that the CMT2A locus is a minor locus for CMT2, additional linkage studies are needed to localize other CMT2 loci, and Cx32 mutations may be the underlying genetic defect in some CMTS families.

The authors report an Italian family with autosomal-dominant Charcot–Marie–Tooth disease (CMT) in which there were giant axons in the sural nerve biopsy. Linkage to the known CMT2 loci (CMT2A, CMT2B, CMT2D, CMT2F) and mutations in the known CMT2 genes (Cx32, MPZ, NEFL), GAN, NEFM,and CMT1A duplication/HNPP deletion were excluded. This family with CMT and giant axons has a pathologic and genetic entity distinct from classic CMT.

Generalized epilepsy with febrile seizures plus (GEFS) is a clinically and genetically heterogeneous syndrome with childhood onset, characterized by febrile seizures (FS) and a variety of afebrile epileptic seizure types. The authors performed a mutational analysis of SCN1Bon 74 unrelated probands with GEFS, FS, or FS plus (FS). In a family with FS and early-onset absence epilepsy, a mutation was identified that predicts a deletion of five amino acids in the extracellular immunoglobulin-like domain of SCN1B and potential loss of function. SCN1Bmutations are associated with GEFS and may have a role in the elicitation of absence seizures.

We previously reported a large Charcot-Marie-Tooth family not linked to the Duffy blood group marker, supporting the existence of genetic heterogeneity in this neuropathy. In order to investigate the possibility of another disease locus on chromosome 1, we analyzed this family further, using DNA polymorphisms of 6 genes. Absence of linkage makes a second disease locus on chromosome 1 unlikely.

Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1gene (c.1160G→C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.

The authors review the molecular genetics and pathophysiology of hereditary recurrent focal neuropathies hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). Significant progress in the understanding of HNPP and HNA has been achieved. HNPP and HNA are distinct clinical and pathologic disease entities with autosomal dominant inheritance. Molecular genetic studies have shown that HNPP and HNA are located on chromosome 17 but at distinct genetic loci (17p11.2 for HNPP, 17q25 for HNA). The 1.5 megabase deletion in 17p11.2 is the major cause of HNPP. This interstitial deletion causes the complete loss of one allele of the peripheral myelin protein 22 (PMP22) gene. Interestingly, rare HNPP patients are found without the 1.5 megabase deletion. However, these patients have distinct mutations in the PMP22gene resulting in altered expression of the PMP22protein. Current molecular genetic tests and clinical guidelines allow improved diagnosis, prognosis, and genetic counseling for patients with HNPP. Such tests are not available for HNA, because the disease-causing gene remains unknown. Molecular genetic advances in HNPP and HNA, as well as the study of transgenic animal and cellular models, will provide a more precise understanding of the disease mechanisms and will lead to the development of effective therapeutic tools for patients with inherited and sporadic recurrent peripheral neuropathies.

To elucidate genetic heterogeneity in ulcero-mutilating neuropathy.