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Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, [...]

A study aims to identify the subunit of serine palmitoyltransferase (STP) enzyme, the mutations in which cause hereditary sensory and autonomic neuropathy type 1 (HSAN-1). Results reveal that mutations in the SPTLC2 subunit of STP cause HSAN-1.

Increasing evidence supports the notion that spinal cord microglia activation plays a causal role in the development of neuropathic pain after peripheral nerve injury; yet the mechanisms for microglia activation remain elusive. Here, we provide evidence that NADPH oxidase 2 (Nox2)-derived ROS production plays a critical role in nerve injury-induced spinal cord microglia activation and subsequent pain hypersensitivity. Nox2 expression was induced in dorsal horn microglia immediately after L5 spinal nerve transection (SNT). Studies using Nox2-deficient mice show that Nox2 is required for SNT-induced ROS generation, microglia activation, and proinflammatory cytokine expression in the spinal cord. SNT-induced mechanical allodynia and thermal hyperalgesia were similarly attenuated in Nox2-deficient mice. In addition, reducing microglial ROS level via intrathecal sulforaphane administration attenuated mechanical allodynia and thermal hyperalgesia in SNT-injured mice. Sulforaphane also inhibited SNT-induced proinflammatory gene expression in microglia, and studies using primary microglia indicate that ROS generation is required for proinflammatory gene expression in microglia. These studies delineate a pathway involving nerve damage leading to microglial Nox2-generated ROS, resulting in the expression of proinflammatory cytokines that are involved in the initiation of neuropathic pain. spinal nerve transection |sulforaphane doi/ 10.1073/pnas.1009926107

Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including DIAPH3. DNA sequencing of DIAPH3 revealed a c.-172G > A, g. 48G > A mutation in a highly conserved region of the 5' UTR. The c.-172G > A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid ceil lines from affected individuals. Likewise, a significant increase ([approximately equal to]1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G > A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitutively active form of diaphanous protein in the auditory organ of Drosophila melanogaster recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene OTOF and the pejvakin gene PJVK, are known to underlie nonsyndromic auditory neuropathy. Genetic testing for DIAPH3 may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy. genetics | 5'UTR | formin | overexpression | DIAPH1 doi/ 10.1073/pnas.1003027107

A study to trace the gene which could be the cause of multicystic kidney diseases, cramps and aneurysms in humans is conducted. Results indicate that mutation of the COL4A1 gene as the possible cause of the conditions.

Schwann cell-derived peripheral myelin protein-22 (PMP-22) when mutated or overexpressed causes heritable neuropathies with a previously unexplained 'gain-of-function' endoplasmic reticulum (ER) retention phenotype. In wild-type sciatic nerves, PMP-22 associates in a specific, transient ([t.sub.1/2] [approximately equal to] 11 min), and oligosaccharide processing-dependent manner with the lectin chaperone calnexin (CNX), but not calreticulin nor BiP. In Trembler-J (Tr-J) sciatic nerves, prolonged association of mutant PMP-22 with CNX is found ([t.sub.1/2] > 60 min). In 293A cells overexpressing PMP-[22.sup.Tr-J], CNX and PMP-22 colocalize in large intracellular structures identified at the electron microscopy level as myelin-like figures with CNX localization in the structures dependent on PMP-22 glucosylation. Similar intracellular myelin-like figures were also present in Schwann cells of sciatic nerves from homozygous Trembler-J mice with no detectable activation of the stress response pathway as deduced from BiP and CHOP expression. Sequestration of CNX in intracellular myelin-like figures may be relevant to the autosomal dominant Charcot--Marie--Tooth-related neuropathies. endoplasmic reticulum quality control | myelinopathy | hereditary neuropathy | Trembler | Charcot-Marie-Tooth disease

Background: Glaucomatous neuropathy is a type of cell death by apoptosis. The p53 gene is one of the regulatory genes of apoptosis. Recently, p53 codon 72 polymorphism has been extensively [...]

Mutations in the gene encoding the peripheral myelin protein 22 (PMP22), a tetraspan protein in compact peripheral myelin, are one of the causes of inherited demyelinating peripheral neuropathy. Most PMP22 mutations alter the trafficking of the PMP22 protein in Schwann cells, and this different trafficking has been proposed as the underlying mechanism of the disease. To explore this problem further, we compared the aggregation of wild-type Pmp22 with those of the two Pmp22 mutations found in Trembler (Tr) and Trembler J (TrJ) mice. All three Pmp22s can be crosslinked readily as homodimers in transfected cells. Wild-type Pmp22 also forms heterodimers with Tr and TrJ Pmp22, and these heterodimers traffic with their respective mutant Pmp22 homodimers. All three Pmp22s form complexes larger than dimers with Tr Pmp22 especially prone to aggregate into high molecular weight complexes. Despite the differences in aggregation of Tr and TrJ Pmp22, these two mutant Pmp22s sequester the same amount of wild-type Pmp22 in heterodimers and heterooligomers. Thus, the differences in the phenotypes of Tr and TrJ mice may depend more on the ability of the mutant protein to aggregate than on the dominant-negative effect of the mutant Pmp22 on wild-type Pmp22 trafficking.

Results reveal that Charcot-Marie-Tooth disease type 2A is a result of a loss-of-function mutation in the motor domain of the KIF1Bbeta gene, encoding the kinesin superfamily motor protein.

A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease (ARCMT2), , is discussed. The disease maps to chromosome 1q21.2-q21.3 based on a study of a large consanguineous Moroccan ARCMT2 family with nine sibs affected. The disease is known to be clinically, neuropathologically, electrophysiologically, and genetically heterogeneous and actually is a group of peripheral nervous system disorders. CMT is the most common, hereditary motor/sensory neuropathy, but the ARCMT2 type is very rare and is found in families with established consanguinity only.

Congenital insensitivity to pain with anhidrosis (CIPA) is associated with mutations in the TRKA gene, which encodes a high-affinity tyrosine kinase receptor for nerve growth factor. Eleven new TRKA mutations have been identified in seven families affected with CIPA. The families are from Kuwait, Italy, United Arab Emirates, Spain and Canada. The mutations occur in both the extracellular domain and the intracellular signal-transduction domain of the gene.

The hotspot for homologous recombination in hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A) has been narrowed to a 557-bp sequence on chromosome 17p11.2-p12. A polymerase chain reaction strategy was used for amplification of recombinant CMT1A-REP from patients with HNPP and controls. Many independent meiotic recombination events occurring at a single locus have been examined.

An unusual mutation affecting nucleotide 14482 of the mitochondrial ND6 gene has been found in a Turkish matrilineal pedigree associated with bilateral optic atrophy. The optic neuropathy is consistent with Leber hereditary optic neuropathy (LHON), but the three previously identified LHON mutations were not found. There is strong evidence that the 14482 mutation can be considered the primary etiological source of the optic neuropathy in this family.

Genetic analysis of people with Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) has detected inherited DNA mutations that may cause these diseases. Both CMT1A and HNPP are inherited nerve diseases that result in muscular atrophy. The majority of CMT1A patients appear to have a DNA duplication of a 1.5-megabase (Mb) section on chromosome 17. Similarly, HNPP is associated with a 1.5-Mb deletion in chromosome 17. The duplication and deletion are valuable genetic markers that will be useful for clinical evaluation and diagnosis. Molecular diagnosis can be accomplished by evaluation of DNA fragment differences, the presence or absence of genes, and the presence of new DNA junction fragments. These markers will enable patients to be diagnosed with a simple blood test and will be important for prognosis and treatment of resulting disease.

The 22-kDa peripheral myelin protein (PMP-22) is a protein specific to the peripheral nervous system with possible associations to the trembler (Tr) mutation in mice. The pmp-22 gene coding for PMP-22 was mapped to mouse chromosome 11, 4.4 centimorgans (cM) distal to the granulocyte-macrophage colony-stimulating factor gene, and 2.2 cM proximal to the skeletal muscle myosin heavy chain isoform gene. These results demonstrate the identity of pmp-22 to the Tr locus. The results also indicate that pmp-22 is involved in different forms of peripheral neuropathies.

Charcot-Marie-Tooth neuropathy, also known as hereditary motor and sensory neuropathy (HMSN) type I, is a somewhat diverse genetic disorder. The condition generally begins in the second or third decade of life, and involves slowly progressive weakness and atrophy of distal (extremity) muscles. HMSN type I has very slow nerve conduction velocities. The disease may be sporadic. It may be inherited as a sex-linked trait, and as either a dominant or recessive trait. Most families with a history of HMSN type I seem to carry the gene on chromosome 17, but the HMSN type I gene is located on chromosome I in a few families, and may even be found on other chromosomes in other families. Many genetic disorders have incomplete penetrance; this term is applied by geneticists to cases where some individuals carrying the gene have different characteristics than other individuals with apparently the same gene. The concept of penetrance has been invoked to explain why there is variability in the age of onset of HMSN type I and why all individuals are not equally affected. Using electrophysiological techniques, the authors evaluated patients from three families with histories of HMSN type I apparently linked to chromosome 17. They found that when slow nerve conduction velocities were used as the diagnostic criteria, the variable ''penetrance'' disappeared. All the individuals were affected at an early age, whether the symptoms appeared at that age or not. Furthermore, the slow-down of conduction was essentially complete at an early age; the decreased velocity did not worsen with age, but the rate could vary among individuals. Graphical plots of the nerve conduction velocities revealed two distinct groups without overlap. Two asymptomatic individuals were in the abnormal nerve conduction group. The results indicate that although the clinical signs of HMSN type I may vary among individuals, the fundamental pathological process of the disorder is completely penetrant, that is, all individuals carrying the dominant gene express the fundamental nerve conduction defect. (Consumer Summary produced by Reliance Medical Information, Inc.)

A family has been identified in which 13 of the 31 family members examined have hereditary motor and sensory neuropathy (HMSN), an inherited disorder of the peripheral nerves. What makes this family different, however, is that 8 of the 13 affected family members also have unmistakable signs of myotonic dystrophy (MyD). The majority of family pedigrees of HMSN show signs of linkage to chromosome 17. The disorder is heterogeneous, however, and some families with similar symptoms show linkage of their disorder to the Duffy blood group locus on chromosome 1. However, the gene for myotonic dystrophy is on chromosome 19, extremely close to the gene for apolipoprotein C2. Investigation of this family revealed no signs that the inherited disorder was located on chromosome 17. Using DNA markers for the apolipoprotein C2 gene, it was found that all affected individuals inherited a unique form of the gene which could not be found in the unaffected members of the family. This strongly suggests that the genetic disorder in this family is closely linked to the apolipoprotein C2 gene, and is located on chromosome 19. Since HMSN is heterogeneous, it is possible that there exists an HMSN gene which is closely linked to the MyD gene, and that eight of the family members in the present kinship have inherited both genes. However, a more plausible explanation is that some mutations of the MyD gene may result in symptoms of HMSN. It is known that different family groups with HMSN often have different clinical forms of the disease. The authors speculate that an unusual mutation in this family causes symptoms of HMSN, and in a few individuals results in the symptoms associated with MyD, as well. (Consumer Summary produced by Reliance Medical Information, Inc.)

Spinocerebellar degenerative disorders constitute a large homogeneous group of genetic diseases. Inheritance is usually easy to determine, and most often occurs by a simple Mendelian mechanism, either autosomal dominant or recessive. Beyond that, however, the situation rapidly becomes more complex. Not only do the characteristics differ among different disorders, but affected members of the same family sometimes show wide variations. The diagnosis of a particular familial degenerative disorder can only be made by the careful compilation of a multitude of clinical observations. In most cases, the underlying genetic defect has not been identified. In these disorders, particular neurons degenerate without evidence of inflammatory reaction; consequently, they are generally called systemic degeneration. A common feature among many spinocerebellar degeneration syndromes is ''dying back'', in which the nerve axon begins to degenerate at the end organ, and the generation proceeds backwards until the cell body is affected. In studying a family with a spinocerebellar degeneration disorder, investigators found an array of signs and symptoms that are consistent with a diagnosis of spinopontine atrophy. Twenty-five members of this family of German extraction, spanning three generations, appear to have had the disorder. Detailed clinical information was available for 12 patients. Much of the data was derived from three family members for whom detailed neuropathological material became available at autopsy. The affected family members had symptoms of progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscle atrophy. The disease, which was inherited as an autosomal dominant trait, was usually noted at an average age of 40 years. Neuropathological observations included atrophy in the basis pontis and in the spinocerebellar tracts. Clark's columns, anterior horn neurons (known as spinal motor neurons), and the fasciculus gracilis were also affected. This pattern is similar to that observed in Machado-Joseph disease, which was first identified in Portuguese and Azorean families. The authors suggest that the present case study may represent another instance of Machado-Joseph disease occurring in a family of non-Portuguese extraction. (Consumer Summary produced by Reliance Medical Information, Inc.)

Inherited peripheral nerve disorders in children are generally not treatable. In contrast, chronic inflammatory demyelinating polyneuropathy, an acquired disease affecting peripheral nerves, may respond to treatment with corticosteroids. In general, a family history of neuropathy suggests that the disorder is inherited, and that treatment will be to no avail. However, three cases are now reported in which a neuropathy in children seems to have both genetic and acquired components. In all three cases, there was a family history of nerve disorders. However, the presence of certain features of the cases suggested the presence of an acquired demyelinating disorder (characterized by loss of the myelin sheath which covers the axons of nerves). These features include rapid onset or relapsing course, some electrophysiological features, including blockage of the transmission of nerve impulses, and signs of inflammation, as observed in nerve tissue biopsies. All three patients responded to treatment with prednisone. Most symptoms resolved, although some weaknesses remained. The authors suggest that these cases represent the coexistence of an inherited neuropathy with an acquired chronic inflammatory demyelinating polyneuropathy. Since the inflammatory condition is treatable with corticosteroids like prednisone, it is important that clinicians not be blinded to the presence of the acquired disorder by the indications of the inherited one. It is tempting to speculate that the acquired disorder in these patients arises, in some way, from the inherited disorder, or perhaps results from an increased susceptibility. However, in the present cases, the physiologic relationship between the disorders, if any, cannot be determined. Furthermore, any pathologic mechanisms which might relate the two are as yet hypothetical. (Consumer Summary produced by Reliance Medical Information, Inc.)