Micaela Milani

Four novel cases of periaxin-related neuropathy and review of the literature

Objective: To report 4 cases of autosomal recessive hereditary neuropathy associated with novel mutations in the periaxin gene (PRX) with a review of the literature. Periaxin protein is required for the maintenance of peripheral nerve myelin. Patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4F) or Déjèrine-Sottas neuropathy (DSN). Only 12 different mutations have been described thus far. Methods: Case reports and literature review. Results: Four patients from 3 unrelated families (2 siblings and 2 unrelated patients) were affected by an early-onset, slowly progressive demyelinating neuropathy with relevant sensory involvement. All carried novel frameshift or nonsense mutations in the PRX gene. The 2 siblings were compound heterozygotes for 2 PRX null mutations (p.Q547X and p.K808SfsX2), the third patient harbored a homozygous nonsense mutation (p.E682X), and the last patient had a homozygous 2-nt insertion predicting a premature protein truncation (p.S259PfsX55). Electrophysiologic analysis showed a severe slowing of motor nerve conduction velocities (MNCVs, between 3 and 15.3 m/s) with undetectable sensory nerve action potentials (SNAPs). Sural nerve biopsy, performed in 2 patients, demonstrated a severe demyelinating neuropathy and onion bulb formations. Interestingly, we observed some variability of disease severity within the same family. Conclusions: These cases and review of the literature indicate that PRX-related neuropathies have early onset but overall slow progression. Typical features are prominent sensory involvement, often with sensory ataxia; a moderate-to-dramatic reduction of MNCVs and almost invariable absence of SNAPs; and pathologic demyelination with classic onion bulbs, and less commonly myelin folding and basal lamina onion bulbs.

Rapid progression of late onset axonal Charcot–Marie–Tooth disease associated with a novel MPZ mutation in the extracellular domain

Myelin protein zero (MPZ) is a major component of compact myelin in peripheral nerves where it plays an essential role in myelin formation and adhesion. MPZ gene mutations are usually responsible for demyelinating neuropathies, namely Charcot–Marie–Tooth (CMT) type 1B, Déjèrine–Sottas neuropathy and congenital hypomyelinating neuropathy. Less frequently, axonal CMT (CMT2) associated with MPZ mutations has been described. We report six patients (one sporadic case and five subjects from two apparently unrelated families) with a late onset, but rapidly progressive, axonal peripheral neuropathy. In all patients, molecular analysis demonstrated a novel heterozygous missense mutation (208C>T) in MPZ exon 2, causing the Pro70Ser substitution in the extracellular domain. The diagnosis of CMT2 associated with MPZ mutations should be considered in both sporadic and familial cases of late onset, progressive polyneuropathy. The mechanism whereby compact myelin protein mutations cause axonal neuropathy remains to be elucidated.

Novel mutations in the GDAP1 gene in patients affected with early-onset axonal Charcot-Marie-Tooth type 4A

We report a detailed study of eight patients from four Italian families presenting with autosomal recessive axonal Charcot-Marie-Tooth disease (AR-CMT2), characterized by early-onset and progressive severe weakness of all limbs. Vocal cord paresis was present in two cases. Sural nerve biopsy performed in three patients showed a severe neuropathy characterized by a predominant axonal involvement. Five novel mutations (p.Gln99stop, p.Gln122Lys, p.Arg125stop, p.Val219Asp, p.Asn297Lys) and one previously reported mutation (p.Leu239Phe) were identified in GDAP1 gene. GDAP1 mutations should be considered both in recessive and sporadic cases of early-onset axonal CMT.

Does CMT1A homozygosity cause more severe disease with root hypertrophy and higher CSF proteins

Charcot-Marie-Tooth type 1A (CMT1A) is associated with a peripheral myelin protein-22 ( PMP22 ) gene duplication on chromosome 17p11.2.1 CMT1A patients have three PMP22 copies and a gene dosage effect, leading to increased PMP22 protein expression, is the hypothesized pathogenic mechanism. Homozygosity for the duplication has been reported in patients from three families, with both parents carrying the duplication and transmitting the mutation to their offspring, who had PMP22 tetrasomy and variable disease severity.1-3⇓⇓ We report a homozygous CMT1A patient with rather severe disease, high CSF proteins, and astonishing root hypertrophy. The patient is a 45-year-old man born to first-cousin parents. His parents, two sisters, one brother, and two sons had pes cavus and lower limb weakness (see figure E-1A on the Neurology Web site). He developed pes cavus and walking difficulties at age 11 years, scoliosis at age 16, and slowly progressive lower limb weakness until age 42, when he had more rapid worsening with difficulty climbing stairs, loss of balance, and hand weakness. Hearing loss started at age 33 years. On admission, he had marked foot deformities (walking with support), moderate scoliosis, bilateral hearing loss, muscle wasting and weakness (severe distally in lower …

Mutational mechanisms in MFN2-related neuropathy: compound heterozygosity for recessive and semidominant mutations.

Mitofusin‐2 (MFN2) mutations are the most common cause of autosomal dominant axonal Charcot‐Marie‐Tooth disease (CMT, type 2A), sometimes complicated by additional features such as optic atrophy (CMT6) and upper motor neuron involvement (CMT5). Several pathogenic mutations are reported, mainly acting in a dominant fashion, although few sequence variants behaved as recessive or semidominant in rare homozygous or compound heterozygous patients. We describe a 49‐year‐old woman with CMT5 associated with compound heterozygosity for two MFN2 variants, one already reported missense mutation (c.748C>T, p.R250W) and a novel nonsense sequence change (c.1426C>T, p.R476*). Her mother, carrying the p.R250W variant, had very late‐onset minimal axonal neuropathy, whilst the father harboring the nonsense sequence change had neither clinical nor electrophysiological neuropathy. The missense mutation is likely pathogenic according to in silico analyses and a previous report, while the nonsense variant is predicted to behave as a null allele. The p.R250W variant behaves as semidominant by causing only a mild, almost subclinical, neuropathy when heterozygous; the nonsense mutation in the father was phenotypically silent, suggesting that haploinsufficiency for MFN2 is not disease causative, but was deleterious in the daughter who had only one active mutated MFN2 allele.

X-linked Charcot-Marie-Tooth type 1: Stroke-like presentation of a novel GJB1 mutation

X‐linked Charcot‐Marie‐Tooth type 1 (CMTX1) is the second most common type of CMT and is caused by mutations in the Gap‐Junction Beta‐1 gene (GJB1), encoding connexin 32 which is expressed in Schwann cells as well as in oligodendrocytes. More than 400 GJB1 mutations have been described to date. Many mutation‐carrier males have subclinical central nervous system (CNS) involvement, a few show mild CNS clinical signs, whereas only rarely overt though transient CNS dysfunction occurs. We report a 29‐year‐old man with CMTX1 who, at 16 years, showed short‐lived CNS symptoms with transitory white matter abnormalities on cerebral magnetic resonance imaging (MRI) as first clinical presentation of a novel GJB1 mutation (p.Gln99_His100insGln). He had three consecutive episodes of right hemiparesis, together with sensory loss in the paretic limbs and expressive aphasia, all lasting a few hours, over a 2‐day period, with concurrent white matter hyperintensity on MRI. These “stroke‐like” episodes occurred just after arriving at sea level, after travelling from home at 700 m of altitude. Only a few years later did symptoms of peripheral neuropathy appear. In conclusion, CMTX1 should be included in the differential diagnosis of diseases characterized by transient CNS symptoms and white matter abnormalities on MRI.

Co-occurrence of amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2A in a patient with a novel mutation in the mitofusin-2 gene

Mitofusin-2 gene (MFN2) mutations cause Charcot-Marie-Tooth type 2A (CMT2A), sometimes complicated by additional features such as optic atrophy, hearing loss, upper motor neuron signs and cerebral white-matter abnormalities. Here we report, for the first time, the occurrence of motor neuron disease, consistent with amyotrophic lateral sclerosis (ALS), in a 62-year-old woman affected by early-onset slowly progressive CMT2A, due to a novel MFN2 mutation. After age 60, rate of disease progression changed and she rapidly developed generalised muscle wasting, weakness, and fasciculations, together with dysarthria and dysphagia. Clinical features, EMG findings, and fast progression were consistent with ALS superimposed on CMT.

A novel founder mutation in the MFN2 gene associated with variable Charcot–Marie–Tooth type 2 phenotype in two families from Southern Italy

Charcot–Marie–Tooth (CMT) disease is the most common hereditary neuropathy. CMT falls into two main forms: the demyelinating CMT type 1 with decreased nerve conduction velocities and the axonal CMT type 2. CMT2 is further subtyped by linkage analysis into >10 loci, with eight genes identified. Recently, mutations in the mitochondrial fusion protein 2 ( MFN2 ) gene were reported in families with CMT2A1 and additional mutations have been detected in other studies, bringing to 42 the total number of different MFN2 mutations described thus far.2–4 In the current study, we report a novel MFN2 mutation shared by two apparently unrelated CMT2 families originating from the same area in Southern Italy. Vertical transmission and male-to-male inheritance were documented in both families, indicating that CMT2 segregates as an autosomal dominant trait. In family 1, 14 affected individuals were identified in four generations (three deceased before the study). After giving informed consent, eight affected individuals and 12 unaffected family members were examined by neurologists and enrolled in the genetic study. All affected individuals showed bilateral pes cavus, lower extremity wasting and steppage gait; only two of eight affected family members (IV-6, IV-7) complained of leg pain. Electrophysiological examination revealed decreased compound motor action potential (CMAP) and sensory action potential (SAP) amplitudes and mildly slowed motor and sensory nerve conductions that were consistent with …

Double-trouble in pediatric neurology: Myotonia congenita combined with charcot–marie–tooth disease type 1a

Myotonia congenita (MC) is a rare muscle disorder that may be transmitted as either autosomal dominant (Thomsen disease) or recessive (Becker disease) traits, due to mutations in the chloride channel voltagesensitive 1 (CLCN1) gene located on chromosome 7q35. Charcot–Marie–Tooth disease (CMT) is a genetically heterogeneous hereditary neuropathy, and CMT1A is the most common form, caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Because the estimated prevalence of MC is between 7 and 10 per 100,000 population and CMT has a prevalence of 40 per 100,000 population, the theoretical chance of inheriting both diseases is extremely low. We describe the case of a boy who is now age 16 years. He was born to apparently unrelated parents and presented with clumsy gait and frequent falls from the first years of life, progressive gait stiffness, running difficulty, and weakness in proximal upper and lower limbs. At age 11 he showed an unusual association of myopathic and neuropathic signs, including mild distal atrophy, weakness in proximal and distal muscles, reduced tendon reflexes, and evidence of generalized myotonia, with slow and painful muscle relaxation after contraction and a “warm-up” phenomenon with repeated motor activity. Needle electromyography revealed increased insertional and spontaneous activity, marked repetitive discharges of trains of motor unit action potentials, and sustained runs of positive waves or runs of small triphasic potentials consistent with myotonic discharges in proximal and distal muscles (Fig 1a). Mildly reduced motor and sensory conduction velocities (median nerve 42 m/s, sural nerve 40 m/s), increased distal motor latency (median 4.8 ms), and reduced sensory amplitude (sural 7.3 lV) were also present. Electrodiagnostic studies in both asymptomatic parents disclosed a demyelinating polyneuropathy in the father and mild myotonia in the mother. Direct sequencing of CLCN1 in the proband revealed the presence of 2 known heterozygous mutations: a splice mutation c.18013A>T in intron 1, and a missense mutation c.1970T>C in exon 17 (Fig. 1b). PMP22 analysis disclosed the presence of a 17p11.2-12 duplication. We thus demonstrated the CLCN1 gene c.18013A>T mutation in the mother and the p.L657P mutation in the father, who also carried the 17p11.212 duplication in the PMP22 gene (Fig. 1c). These results allowed us to confirm the diagnosis of 2 combined diseases, recessive Becker MC and dominant CMT1A. Two separate gene mutations in different neuromuscular disorders, including CMT, have been reported in a limited number of cases, and we now report the association of MC with CMT1A. There are too few “doubletrouble” cases to define whether concomitant genetic conditions modify the severity and progression of the 2 diseases to produce more severe phenotypes, and we cannot predict whether this condition in our patient could lead to more severe clinical impairment with age. We suggest that clinicians consider that, in the presence of unusual clinical features and a negative family history, there is a possible combination of 2 rare neuromuscular diseases. This can have a significant impact on medical care and genetic counselling. Written informed consent for DNA storage and use for genetic analysis and research purposes was obtained from the patient and his relatives, as required by the ethics committee of the Foundation Neurological Institute “Carlo Besta.”

Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy

Mutations in myelin protein zero (MPZ) protein result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms. In some patients, neuropathic pain can be a prominent symptom, making the diagnosis challenging mainly in those with other risk factors for neuropathy. We describe a 77‐year‐old woman with impaired glucose tolerance presenting with rapidly progressive axonal neuropathy leading to excruciating pain and severe weakness of lower limbs within 2 years from the onset. Her son abruptly complained of similar painful symptoms at the age of 47 years. Molecular analysis revealed a novel heterozygous missense mutation (c.106A>G) in MPZ exon 2, causing the substitution of arginine‐36 with glycine in the extracellular domain. Our observation suggests that MPZ‐related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.