Recurrent Focal Neuropathy Research Articles

Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene

The peripheral myelin protein 22 gene (PMP22) encodes an intrinsic membrane protein of compact myelin. Duplication or deletion of PMP22 causes the most common autosomal dominant neuropathies, Charcot-Marie-Tooth disease type 1A or hereditary neuropathy with liability to pressure palsies. Charcot-Marie-Tooth disease type 1A is a hypertrophic de-remyelinating neuropathy manifesting with peroneal muscular atrophy and uniform, marked, slowing of nerve conduction velocities. Hereditary neuropathy with liability to pressure palsies is a recurrent focal neuropathy with sausage-like myelin thickening (tomacula) and non-uniform nerve conduction velocity changes. Missense or nonsense mutations also cause more severe Charcot-Marie-Tooth disease type 1A forms of infancy or hereditary neuropathy with liability to pressure palsies, but they are presumably very rare. We performed a mutational scanning of PMP22 in 229 index patients (46 familial, 183 isolated) referred for suspected inherited neuropathy. The series included 125 cases with hereditary neuropathy with liability to pressure palsies (mean age 42.5 years), 47 cases with Charcot-Marie-Tooth disease type 1A (motor nerve conduction velocities at median nerve below 38 m/s) (mean age 40.7 years) and 57 cases with Charcot-Marie-Tooth with unknown nerve conduction velocities (mean age 43 years). Preliminary molecular studies ruled out PMP22 duplication or deletion or mutations in a comprehensive panel of Charcot-Marie-Tooth genes. Mutational scanning of PMP22 was done by denaturing high performance liquid chromatography and automated nucleotide sequencing. To investigate the molecular basis of phenotype-to-genotype correlations, we performed a transcriptional analysis of PMP22 using reverse-transcriptase polymerase chain reaction and quantitative real-time polymerase chain reaction in two phenotypically divergent nerve biopsies. Ten patients harboured eight micromutations of PMP22 including four novel changes. In six familial and three sporadic cases, detected mutations caused premature or delayed stop codons and were associated with hereditary neuropathy with liability to pressure palsies; the related pathological pictures ranged from classical tomaculous neuropathy to a mild demyelinating neuropathy with atypical non-tomaculous myelin thickenings. In a single family a c.179-2A> G mutation affecting the splice acceptor site of intron 2 cosegregated with a Charcot-Marie-Tooth disease type 1A-like syndrome and a peculiar pathological picture of demyelinating neuropathy without Charcot-Marie-Tooth disease type 1A-like classical onion bulbs or tomacula. Transcriptional analysis of a novel c.174_178 + 7delAAACGGTGAGGC deletion involving exon 2 and intron 2 demonstrated an unstable mutant transcript leading to a p.Asn59GlyfsX12 change; the mutation represented a null allele and caused a typical tomaculous hereditary neuropathy with liability to pressure palsies. The Charcot-Marie-Tooth disease type 1-like c.179-2A > G allele led to a stable transcript with an in-frame deletion of exon 3 (p.Glu60_Ala106del); the predicted shorter protein could exert variable molecular effects. In conclusion, micromutations of PMP22 cause a clinical and pathological continuum of demyelinating neuropathies that may include atypical phenotypes.

Genomic organization and mutation analysis of three candidate genes for hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy (HNA) is an autosomal-dominant inherited recurrent focal neuropathy affecting mainly the brachial plexus. In this study we report the genomic structure and mutation analysis of three candidate genes: sphingosine kinase 1 (SPHK1); tissue inhibitor of metalloproteinase 2 (TIMP2); and cytoglobin (CYGB). We did not find any disease-associated mutations, indicating that HNA is not caused by point mutations in these genes. However, we identified several sequencing errors in the cDNA of SPHK1 as well as seven novel single-nucleotide polymorphisms.

Hereditary neuralgic amyotrophy (HNA) is genetically heterogeneous

Hereditary Neuralgic Amyotrophy (HNA) is an autosomal dominantly inherited recurrent focal neuropathy affecting mainly the brachial plexus. Linkage to markers on chromosome 17q25 was found in 1996 and subsequent reports confirmed linkage of HNA to this locus. Recently a family with a chronic undulating rather than remitting‐relapsing clinical course of HNA was described by a Dutch group. This family did not have linkage to the 17q25 locus. Here we describe for the first time clinically and genetically two families with classic remitting‐relapsing HNA that are not linked to the previously described HNA locus on chromosome 17q25. These results demonstrate that clinically homogeneous classical HNA is genetically heterogeneous.

Hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy (HNA) belongs to the group of recurrent focal neuropathies, the other major representative being hereditary neuropathy with liability to pressure palsies. The search for the HNA gene has now focused on a locus on chromosome 17q24-q25. Most HNA families show linkage to this locus, but recent evidence indicates that HNA is genetically heterogeneous. Detailed analysis of these unlinked families has broadened our perception of the HNA phenotype, and currently two different clinical courses can be discerned: the classical relapsing-remitting course and a chronic undulating course. After 5 years of molecular genetic research, this disease remains enigmatic. At present, we can only speculate how such very diverse stimuli as immunizations, childbirth, infections, strenuous exercise, and immobilization can trigger painful attacks of brachial plexus palsies in genetically susceptible individuals.

Guidelines for diagnosis of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy [1]. HNPP patients present with variously located recurrent peripheral nerve palsies, or sensory loss, often precipitated by minor trauma or compression. The dysfunction is painless, distinguishing HNPP from another inherited recurrent focal neuropathy, namely hereditary neuralgic amyotrophy [2,3]. Usually the onset is acute, but progressive weakness may occur. In most cases, patients recover within days or weeks, but relapses are frequent, and paresis may last for long periods. A number of patients show signs of a symmetrical distal neuropathy without acute nerve palsies [3,4]. Neurological examination reveals weakness and sensory loss in the distribution of affected nerves; tendon re exes are often depressed or abolished, pes cavus is infrequent, scoliosis is rare, and there is no nerve hypertrophy or CNS involvement [1]. HNPP is probably underdiagnosed because of its usually benign course. In addition, about 10±15% of mutation carriers remain clinically asymptomatic, suggesting incomplete penetrance [4,5]. Given the poverty of the clinical ®ndings in HNPP, electrophysiological examination is of great importance for its diagnosis. Nerve conduction studies reveal a characteristic pattern of mildly decreased motor nerve conduction velocities (MNCV), prolonged distal motor latencies (DML) predominantly at nerve entrapment sites, and altered sensory nerve action potentials, even in clinically nonaffected nerves or in asymptomatic at-risk individuals [6]. A simple standardized electrophysiological examination is suf®cient to identify adult gene carriers: bilaterally delayed median DML and reduced sensory velocity in the palmwrist segment, and a delayed DML or reduced MNCV in the peroneal nerve, are highly suggestive of the disease when there is a family history of HNPP [4]. Peripheral nerve biopsies show a characteristic focal sausage-shaped thickening of the myelin sheath in about 25% or less of the internodes [7], which were designated by Madrid and Bradley as `tomacula' [8,9]. The tomaculous changes are not speci®c to HNPP and can occur, even in a higher frequency in Charcot±Marie±Tooth disease or Dejerine±Sottas phenotype [10]. Some patients do not show these speci®c changes, but rather non-speci®c ®ndings with either extensive loss of ®bers, or excessive variability in thickness and length of myelin internodes [1]. However, molecular analysis has not yet been performed in these HNPP patients. An interstitial deletion in the 17p11.2 region is associated with the disorder in most HNPP families [11±16]. This is the same region, designated CMT1A monomer unit, which contains the gene encoding the peripheral myelin protein 22 (PMP22), which is duplicated in the more frequently diagnosed neuropathy, Charcot±Marie±Tooth disease type 1A (CMT1A) [11±16]. Thus, it was hypothesized that unequal crossing-over between chromosome 17 homologues would generate a duplication that could lead to CMT1A, or a deletion that could result in HNPP. This hypothesis was reinforced by the existence of de novo deletions in HNPP patients without affected parents, most of them with a paternal origin [11,13,15], but sometimes with a maternal origin [17±20]. Investigators have postulated a gene dosage effect of PMP22 contained in the CMT1A monomer unit. This hypothesis has been con®rmed by the demonstration that PMP22 protein level expression in myelin correlates with the number of gene copies [21,22]. Moreover, it has recently been shown that PMP22 mRNA level is lower in the sural nerve of HNPP patients compared with normal controls, and correlates with disease severity [23,24]. The causative role of the PMP22 gene has been de®nitely proven by the existence, in rare HNPP patients, of mutations in this gene, probably causing a loss of function Neuromuscular Disorders 10 (2000) 206±208

Hereditary recurrent focal neuropathies

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 PMP22 gene resulting in altered expression of the PMP22 protein. 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.

Genetic refinement of the hereditary neuralgic amyotrophy (HNA) locus at chromosome 17q25.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant, recurrent focal neuropathy. HNA is characterised by episodes of painful brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. Single episodes are commonly preceded by non-specific infections, immunisations or parturition. Mild dysmorphic features and short stature are present in some HNA families, but absolute co-segregation with HNA has not been described. To refine the previously described HNA locus on chromosome 17q25, we performed a genetic linkage study in five HNA families with different geographic origins. Significant linkage was obtained with chromosome 17q24-q25 short tandem repeat (STR) markers in three HNA families and suggestive linkage was found in the other two HNA families. Analysis of the informative recombinations in affected individuals allowed us to reduce the HNA linkage interval to a candidate region of 3.5 cM.

Mutation analysis of a putative sialyltransferase gene, the SFRS2 splicing factor gene and the c-myb ET-locus in two families with hereditary neuralgic amyotrophy (HNA).

HNA is an autosomal dominant recurrent focal neuropathy involving the brachial plexus. The etiology of HNA is unknown but the genetic defect most likely affects a non-neuronal tissue. We previously described linkage to chromosome 17q24-q25 in two HNA-families. Here we report the mutation analysis of two candidate genes: a cDNA encoding a putative sialyltransferase and the SFRS2 splicing factor including the c-myb ET-locus which is encoded on the opposite strand of the SFRS2 gene. The complete protein coding regions of both genes were studied by direct DNA sequencing. We did not find a disease associated mutation indicating that these genes are most likely not involved in the pathogenesis of HNA. However, we identified and characterized a rare AvaII polymorphism in the SFRS2 gene and detected a sequencing error, leading to an amino acid change (Val11Leu) in the published sequence of the putative sialyltransferase.

Refinement of the hereditary neuralgic amyotrophy (HNA) locus to chromosome 17q24-q25.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant, recurrent focal neuropathy characterized by episodes of painful brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. Single episodes are commonly preceded by unspecific infections or immunization, or are associated with parturition. Minor facial dysmorphic features are present in some pedigrees but do not clearly segregate with the disease. To confirm the recently described HNA locus on distal chromosome 17q, we performed a genetic linkage study in an extended Turkish pedigree. We were able to refine the HNA locus on chromosome 17q24-q25 in a 16-cM region.

Charcot-Marie-Tooth syndrome.

Charcot-Marie-Tooth syndrome (CMT) is a group of genetically determined symmetric distal polyneuropathies. The CMT loci are known to map to chromosome 1 (CMT1B), chromosome 17 (CMT1A), the X chromosome (CMTX), and two additional unknown autosomes (CMT1C and CMT2). The most prevalent form is CMT1A, an autosomal dominant demyelinative disorder caused either by a tandem duplication in band p11.2-12 of chromosome 17 (17p11.2-12) with trisomic expression of the peripheral myelin protein-22 (PMP-22) gene or, less frequently, by a missense mutation of PMP-22. Missense mutations in PMP-22 are also responsible for two forms of demyelinative polyneuropathy in mice, trembler and trembler. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent focal neuropathy. In all families thus far studied, patients with HNPP have been found to be monosomic for a segment of chromosome 17p11.2-12. The duplication in CMT1A and deletion in HNPP map to the same region in 17p11.2-12 and are both likely to be consequences of unequal crossing over during germ cell meiosis.

Tomaculous neuropathy presenting as acute recurrent polyneuropathy

Tomaculous neuropathy (TN) is classically associated with the inherited, recurrent focal neuropathies. We report a case of TN manifesting as an acute recurrent polyneuropathy. A 28-year-old woman had 2 episodes of acute, ascending, symmetrical sensorimotor deficit. Teased nerve-fiber preparation confirmed the presence of TN. Extensive investigations failed to reveal other cause for her symptoms. We believe that this case is unique and broadens the clinical spectrum of TN.