A Rett syndrome MECP2 mutation that causes mental retardation in men

Case reports.

Here we describe the clinical history of five siblings (four men and one woman) and their mother, all with the mutation C493T resulting in an A140V substitution (table 1). The pedigree of the family is shown in figure 1. Detailed genetic findings have been reported.9 The extremely poor sociocultural skills of all the members of the family made it difficult to collect detailed information on patients’ developmental milestones.

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Figure 1. (A) Pedigree of the family. Solid symbols denote the mentally retarded patients. (B) Clinical appearance of patients. From left, the subjects are MR50, X307, X308, X309, and MR49.

Patient X309 is a 63-year-old woman with lower limb weakness. Her mother, who died of a heart attack at 69 years of age, was reported to have slight mental retardation. On clinical examination, the patient showed mild mental retardation, genu valgum, distal atrophy and trophic changes of the legs, microcephaly (52 cm), mild micrognathia, clumsy gait, and hyperactive deep tendon reflexes. EMG and nerve conduction velocities (CVs) were in the normal range.

The only daughter (Patient MR49), aged 42 years, had delayed psychomotor development and speech. She attended primary school with poor profit and was married at the age of 26 years. She now works as a domestic helper. Clinical evaluation showed mild mental retardation, slight microcephaly (53 cm), micrognathia, severe myopia, genu valgum, flat foot, mild distal atrophy of all limbs, mild spastic gait, hyperactive deep tendon reflexes, and mild bilateral rhythmic postural hand tremor. Laboratory parameters, including routine blood clinical chemistry, EEG, EMG, nerve CVs, CT scan, brain MRI, and ¹H-MRS were normal. The latter was performed by placing a large volume of interest positioned to include the largest proportion of the brain white matter of both hemispheres and assessing metabolic information in each cubic millimeter of this brain region. The XCI patterns in both the affected women (X309 and MR49) were analyzed for methylation status at the androgen receptor locus and revealed an almost random pattern of inactivation.

Patient X307, aged 40 years, was born preterm. Like the other siblings, he had psychomotor retardation. However, since infancy he was able to walk alone and could speak in a simple fashion. He did not attend school. Recently, the parents noticed progressive gait problems and difficulty in climbing stairs. Clinical and neurologic examination showed a head circumference of 54 cm, flat occiput, large ears, high-arched palate, mild micrognathia, short neck, hyperlaxity of the hands, pes cavus with claw, cold blue feet, postural tremor of the hands, plastic hypertonia of the wrists, distal atrophy of the legs with trophic changes, mild spastic paraparesis, mild gait ataxia, and absent deep tendon reflexes of lower limbs. Speech was rudimentary and dysarthric. Neuropsychological testing was not possible. Funduscopy showed cupping of the optic disks. All laboratory test results (including routine blood chemistry, EEG, EMG, and CV of peripheral nerves, brain MRI, and ¹H-MRS) were normal.

Patient MR48, a man, died suddenly at 39 years of age. No autopsy was performed. The subject had severe mental retardation with progressive gait impairment. Since 23 years of age he was unable to walk unaided. Clinical examination at age 38 years showed mild dysmorphic features similar to those of his brothers, distal atrophy and trophic changes of the legs, severe spastic-ataxic gait, hand tremor, and dysarthric speech. Laboratory investigation results were normal. Brain MRI and ¹H-MRS were not performed.

Patient MR50, male, 32 years of age, has severe mental retardation and motor and language delay. He attended a special school for the mentally retarded but made no progress. A few years ago, he began to have difficulty going down stairs. Clinical examination showed a head circumference of 56 cm, flat occiput, high-arched palate, mild micrognathia, pes cavus, cold, swollen blue feet, distal leg trophic changes, short neck, claw feet, hyperlaxity, distal atrophy of the legs, mild gynecomastia, kyphoscoliosis, mild spastic paraparesis, hyperactive deep tendon reflexes, ankle clonus, and Babinski reflexes. Like his siblings, he had normal laboratory parameters (including EEG, EMG, nerve CV, brain MRI and ¹H-MRS).

Patient X308 is a 27-year-old man with mental retardation and motor and speech delay. He attended a special school for mentally retarded and learned to write a few words, drive a tractor, and help his father on the farm. His clinical phenotype was similar to that of his brothers, with a normal head circumference (55.5 cm), flat occiput, mild micrognathia, high-arched palate, large ears, pes cavus, mild distal atrophy of the legs, clumsy gait, hyperactive deep tendon reflexes, bilateral ankle clonus, and Babinski reflexes. Laboratory investigation results were normal.

Another brother died at 4 years of age due to an accident. He is reported to have been normal.

Discussion.

MECP2 mutations were originally described in a high percentage of patients with classic RTT.3,13,14⇓⇓ RTT is an X-linked progressive neurologic disorder affecting women and characterized by regression of previously acquired skills, loss of speech and purposeful hand use, postnatal microcephaly, stereotyped “hand washing,” autistic features, gait ataxia, and breathing abnormalities. By puberty, most patients stabilize and some may recover certain abilities.15,16⇓ A preserved speech variant of classic RTT was postulated.17

MECP2 mutations also have been reported in phenotypes ranging from atypical RTT to autistic disorder,4,9,11,18⇓⇓⇓ and therefore may not be limited to RTT but implicated in a much broader spectrum of phenotypes.5,19-22⇓⇓⇓⇓

Since our first report of MECP2 mutation in adult men with MRX, other cases have been described, making a total of 22 men, 17 familial and 5 sporadic, with different degree of mental retardation (table 2). In seven cases, including the current family, neurologic features were associated with mental retardation. None of the MECP2 mutations found in men with MRX has previously been reported in RTT (figure 2).

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Figure 2. MECP2 gene mutations reported in men with X-linked mental retardation. MBD = methyl-binding domain; TRD = transcription repression domain. Illustration is not to scale.

The relevance of MECP2 mutational involvement in MRX was emphasized by the recent report of novel missense mutations (E137G, R167W, P399L, and R453Q) in mentally retarded men and the finding of two additional patients carrying the A140V mutation.12 A140V therefore could be the most common MECP2 mutation in men. The relatively high frequency of mutations found in mentally retarded patients suggests that MECP2 could be responsible for nonspecific MRX with a frequency similar to that of fragile X syndrome.12 Although clinical details are lacking in most cases,12 only unremarkable neurologic signs (resting tremor in three of four cases in T36 family, hyperreflexia and moderate hypotrophy in three of seven cases in MRX16 family23) are present in a few patients in association with variable, from slight to severe, mental retardation. All related women, including those carrying the A140V mutation, were normal. The presence of symptomatic carrier women in our family seems to be an important difference (see table 2). Because both studies9,12⇓ found a random XCI pattern in lymphocytes, the dissimilar clinical picture of mutated women could possibly be attributed to differences in neuronal expression resulting from skewed X-inactivation in the brain.

A Belgian family24 in which an MECP2 mutation (Q406X) segregated in affected male members recently was reported.10 In this family, as well as in our family, severe mental retardation in men was associated with progressive neurologic manifestations, including spasticity, ataxia, and involuntary movements. However, there also were many significant differences. The former family had a more complex clinical phenotype, with seizures, absence of speech, macrocephaly, grinding of teeth, choreoathetosis, unexplained diarrhea, sialorrhea, and cataract (one patient). In addition, unlike the heterozygous women of our family, the two female carriers of the Belgian family were described as normal or with borderline intelligence, thus suggesting an X-linked recessive trait, whereas our family simulates an X-linked semidominant trait.

Another man with MECP2 mutation (G428S) recently was reported.11 This patient showed a nonfatal, nonprogressive encephalopathy of neonatal onset, mild dysmorphic features, uncoordinated movements, and mild distal muscular atrophy, but no spasticity. His heterozygous mother was reported to be completely normal.

In our patients, we did not find biochemical, electrophysiologic, or neuroradiologic indicators of MRX associated with MECP2 gene mutations. Even ¹H-MRS examination of the brain, which is very sensitive to cerebral metabolic abnormalities leading to axonal damage or impaired oxidative metabolism, was normal. This might be because of the very mild cerebral abnormalities in patients with these genetic disorders. In contrast, in classic RTT, ¹H-MRS has provided supporting evidence of diffuse gray and white matter impairment, mainly involving the frontal and parietal lobes and insular cortex.25,26⇓ The normal findings on brain MRI reported in the current family and in the other patients,11,12⇓ and autopsy evidence of only mild cortical atrophy found in one subject,24 seem to confirm this hypothesis.

The Italian family reported here confirms this hypothesis and suggests that 1) MECP2 mutations also may be linked to forms of MRX in women that do not fulfill the clinical criteria of classic RTT and its variants, resulting in highly variable severity of symptoms; 2) MECP2 mutations may be a quite common cause of mental retardation in men; 3) in men with MECP2 mutations, mental retardation may be associated with slowly progressive neurologic symptoms, including spasticity, distal muscular atrophy, involuntary movements, and ataxia; and 4) because the phenotypic variability in affected women is attributed mainly to neuronal mosaicism for MECP2 expression resulting from XCI, mutated men may provide insights into the mechanism of MECP2 function.

In our patients, the substitution of a valine for alanine at position 140 may be predicted to alter the secondary structure by shortening the length of the alpha helix domain of MBD. A140V should therefore have a subtle effect on MECP2 through conformational changes, but residual activity should be conserved.

The absence of specific clinical features and the variability of neurologic signs that may result from MECP2 mutations in surviving men are of interest. Mutations of the same gene have been associated with a wide spectrum of clinical features, ranging from syndromic forms to mild, nonspecific disorders,2 because phenotypic differences are related to the type of mutations, age, and additional environmental or genetic factors. As more is discovered about the molecular basis of mental retardation, current classifications can be expected to change and the spectrum of phenotypes of this emerging mental retardation condition will become clearer.