A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 4D (CMT4D), also called Lom-type hereditary motor and sensory neuropathy, is caused by homozygous mutation in the NDRG1 gene (605262) on chromosome 8q24.

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive disorder of the peripheral nervous system characterized by early-onset distal muscle weakness and atrophy, foot deformities, and sensory loss affecting all modalities. Affected individuals develop deafness by the third decade of life (summary by Okamoto et al., 2014).

For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive Charcot-Marie-Tooth disease, see CMT4A (214400).

Kalaydjieva et al. (1996) described an autosomal recessive peripheral neuropathy with deafness and unusual neuropathologic features, initially identified in 14 affected individuals from the 'Gypsy' community of Lom, a small town on the Danube River in the northwest of Bulgaria (see HISTORY). They proposed to refer to the disorder as 'hereditary motor and sensory neuropathy-Lom' (HMSNL). Kalaydjieva et al. (1996) stated that HMSNL is characterized by distal muscle wasting and atrophy, foot and hand deformities, tendon areflexia, and sensory loss. Onset is in the first decade and most patients become severely disabled in the fifth decade. Deafness is an invariant feature of the phenotype and usually develops in the third decade. Conduction velocities in the median, ulnar, tibial, and peroneal nerves are severely reduced in the youngest patients and unattainable after age 15 years. Decreased conduction velocity and compound action muscle potential amplitude are also found proximally, in the axillary and facial nerves. Brainstem auditory evoked potentials are markedly abnormal, with prolonged interpeak latencies consistent with demyelination. Neuropathologic investigations showed that myelinated fibers were severely reduced in number and those that remained were a very small size. The parents of affected individuals were asymptomatic and electrophysiologic investigations failed to detect any abnormality.

Kalaydjieva et al. (1998) reviewed all aspects of the Lom type of HMSN. It begins consistently in the first decade of life with gait disorder followed by upper limb weakness in the second decade and, in most subjects, by deafness which is most often first noticed in the third decade. Sensory loss affecting all modalities is present, both this and the motor involvement predominating distally in the limbs. Skeletal deformity, particularly foot deformity, is frequent. Severely reduced motor nerve conduction velocity indicates a demyelinating basis, which is confirmed by nerve biopsy. The 3 younger patients biopsied showed a hypertrophic 'onion bulb' neuropathy. The hypertrophic changes were not evident in the oldest individual biopsied, and it is likely that they had regressed secondarily to axon loss. In the 8 cases in which brainstem auditory evoked potentials could be recorded, the results suggested demyelination in the eighth cranial nerve and also abnormal conduction in the central auditory pathways in the brainstem.

Merlini et al. (1998) described the same disorder in 4 sibs of an Italian family described as of Gypsy ethnic origin. The parents were clinically normal and apparently nonconsanguineous. Four of 5 children presented foot deformities and hand weakness in the first decade of life. All 4 children began walking late. The 3 oldest children, aged 15, 13, and 11 years, showed distal wasting and weakness in all 4 limbs, which was most marked in the oldest sib. They also showed talipes cavus equinovarus. Tendon reflexes were absent in the legs of all 4 sibs. Mild distal sensory loss was also present. No autonomic nervous system dysfunctions were observed. The 13-year-old patient presented a pure sensorineural hearing loss, while the other 3 sibs showed a mixed pattern, with loss of the stapedial reflex. The affected children were homozygous for the same haplotype, which was identical to the common HMSNL haplotype found in Bulgarian Gypsy patients for 6 markers. One of these markers displayed a rare allele that had also been found in a subset of affected families in Bulgaria.

Navarro and Teijeira (2003) noted that HMSNL is phenotypically similar to the Russe form of hereditary motor and sensory neuropathy (605285), which is also common in the Gypsy population.

Okamoto et al. (2014) reported 3 sibs, born of consanguineous Turkish parents, with CMT4D. The patients had delayed motor milestones in early childhood, with gait instability due to muscle weakness. The disorder was progressive, and patients developed severe distal and mild proximal muscle weakness. Other features included pes cavus, kyphoscoliosis, hammertoes, and claw hands. Sensation was severely diminished distally, and electrophysiologic studies showed loss of sensory nerve action potentials as well as loss of compound action muscle potentials. The patients developed sensorineural deafness in the first decade. Two affected individuals had signs of glaucoma, but this feature may have been unrelated to the CMT phenotype.

Pathologic Findings

King et al. (1999) made ultrastructural observations on sural nerve biopsy specimens from 5 cases of HMSNL. Longitudinal sections showed demyelination/remyelination. Severe progressive axonal loss was conspicuous, but there was no indication of axonal atrophy. Hypertrophic onion bulb changes were present in younger patients which later regressed. The axons were hypomyelinated, and partial ensheathment of axons by Schwann cells was observed. Uncompacted myelin and accumulations of pleomorphic material in the adaxonal Schwann cell cytoplasm were features. An unusual finding was the presence of intraaxonal accumulation of irregularly arranged curvilinear profiles. The amount of endoneurial collagen was markedly increased.

The transmission pattern of CMT4D in the family reported by Okamoto et al. (2014) was consistent with autosomal recessive inheritance.

To map HMSNL, Kalaydjieva et al. (1996) adopted a 2-stage genome screening strategy. During the first stage, analysis for segment sharing was conducted in a selected small subset of the Lom kindred, connected via 5 different paths with an average of 9.5 meiotic steps. The analysis of approximately 30% of the genome identified 2 shared segments, namely D8S257-D8S200 and D8S198-D8S284, which satisfied all screening criteria. During the second stage, the entire pedigrees were analyzed for linkage to 17 markers on 8q, telomeric to D8S257. Two-point linkage analysis provided strong evidence that HMSNL is located on 8q24-qter, between D8S284 and D8S534. The highest lod score of 7.7 was obtained for D8S378 at theta = 0.0. Multipoint lod scores pointed to the D8S284-D8S537 interval as the most likely location for HMSNL with a maximum lod likelihood difference of 6.6 at D8S378. The transmission disequilibrium test (TDT) revealed existence of strong linkage disequilibrium in the interval D8S557-D8S537 (5.3 cM). Kalaydjieva et al. (1996) stated that no myelin genes are known to be located on 8q24. Evidence of linkage to roughly the same region was reported in a black American family with dominantly inherited Dejerine-Sottas neuropathy (145900) (Ionasescu et al., 1996). Taken together, the findings suggested to Kalaydjieva et al. (1996) that allelic mutations in a previously unknown myelin gene on 8q24 may be responsible for different demyelinating phenotypes with recessive as well as dominant modes of inheritance. Haplotype information appeared to indicate that the HMSNL mutation predated the divergence of Bulgarian Gypsies, implying that it should occur in other Gypsy groups within (and probably also outside) Bulgaria. On the basis of linguistic evidence, the Gypsy exodus from India has been dated to around 1000 AD. A phenotype similar to HMSNL, Charcot-Marie-Tooth disease and deafness (214370), has been described in an Indian family.

Kalaydjieva et al. (2000) reduced the HMSNL interval to 200 kb and characterized it by means of large-scale genomic sequencing. Sequence analysis of 2 genes located in the critical region identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene-1 (NDRG1; 605262.0001). NDRG1 is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus. Kalaydjieva et al. (2000) studied expression in peripheral nerve and detected particularly high levels in Schwann cells. Taken together, these findings pointed to NDRG1 having a role in the peripheral nervous system, possibly in the Schwann cell signaling necessary for axonal survival.

In 3 sibs, born of consanguineous Turkish parents, with CMT4D, Okamoto et al. (2014) identified a homozygous 6.25-kb intragenic duplication in the NDRG1 gene (605262.0003). The duplication, which was found by array CGH analysis, segregated with the disorder in the family. RT-PCR studies of patient cells showed that the duplication resulted in a nonsense mutation at codon 223 and decreased levels of NDRG1 mRNA. Breakpoint sequence analysis suggested a replicative mechanism for generating the duplication.

The Gypsies studied by Kalaydjieva et al. (1996) stemmed from a small group of 50 to 100 individuals who moved into Bulgaria from Macedonia and settled in Lom in 1886. Their traditional trade suggested that they belong to the Djambazi, an ethnonym that means 'trading in horses.' The main Djambazi migration to Bulgaria occurred from the west in the 16th century, and the largest number of this group still live in Macedonia and Serbia. The group is highly endogamous; in 1 study of 78 marriages, 70 were contracted within the community, 7 involved an individual from a different area but the same Gypsy group, and 1 (4 generations ago) was reportedly between a Bulgarian man and a Gypsy woman. Consanguineous marriage was not practiced, however, and the closest relationship between the parents in a family with HMSNL was third cousins once removed. In the course of the study, a second cluster comprising 3 families with 6 affected individuals was identified 250 km east of Lom. The affected families belonged to different Gypsy groups and were unaware of any connection to the Lom kindred. Two families were Wallachian Gypsies, a group that has lived for centuries in the Wallachian kingdom to the north of the Danube, in present-day Romania. Wallachian Gypsies speak a Romany dialect that belongs to a stratum different from that of the Djambazi. Their migrations into Bulgaria were dated mainly to the 16th-18th centuries and also to the late 19th-early 20th century. The third kindred from this cluster were Turkish-speaking Muslim Gypsies. Since Gypsies easily adopt the language and the religion of the surrounding populations, the past group identity of this family was difficult to define.

Navarro and Teijeira (2003) provided a detailed review of neuromuscular disorders among the Romany Gypsies.