1. Top of page
  2. Abstract
  3. Discussion
  4. References

The phenotype attributed to MECP2 mutations continues to expand. In addition to classic and variant Rett syndrome, phenotypes include non-specific intellectual disability and autism spectrum disorder in females, and fatal neonatal encephalopathy in males. One particular phenotype of parkinsonism, pyramidal signs, and neuropsychiatric symptoms (PPM-X) has been described only in males. We report on the first female with the A140V MECP2 mutation presenting with late onset cognitive regression, pyramidal symptoms, parkinsonism, and bipolar symptoms. This finding emphasizes the need to consider MECP2 sequencing in females with non-classic Rett phenotypes, particularly those with intellectual disability and neuropsychiatric features.


Parkinsonism, pyramidal signs, and neuropsychiatric symptoms


Rett syndrome

MECP2 mutations have been linked to an increasing range of clinical phenotypes. In females this includes classic and atypical Rett syndrome (RTT), non-specific intellectual disability, and autism spectrum disorder.[1, 2] In males, phenotypes include: fatal neonatal encephalopathy,[3] non-specific intellectual disability,[4] and intellectual disability with parkinsonism, pyramidal signs, and neuropsychiatric symptoms (PPM-X).[5] We present the first report of a female with a PPM-X phenotype caused by a MECP2 mutation, thus expanding the phenotypes associated with mutations in this gene.

We report a 15-year-old female who was referred for neurological assessment at age 13 for subacute behavioral changes and disordered mood. Fully informed written consent was provided by the family for publication of this case report.

Pregnancy and birth history were unremarkable. Gross motor and language development were normal. She began speaking in sentences before the age of 2 and there were no expressive or receptive language concerns. Fine motor development noted difficulties achieving the ability to button, zip, and tie shoelaces. Her handwriting was appropriate for her age. She tended to socialize parallel to her peer group and thrived with routine, but did not meet criteria for autism. Psychological testing was obtained at 6 years of age because of concern regarding her comprehension, retention, writing, and mathematics performance. Testing revealed a severe non-verbal learning disability. Repeat testing at 9 years 6 months revealed an interval decline in her test scores (Table 1).

Table 1. Evidence for cognitive regression by scores on the Wechsler Intelligence Scales for Children (WISC III-IV)
WISC-III and WISC-IVAge 6yaAge 9y 6moaAge 14ya
  1. a

    Canadian centile norms.

Verbal Scale80
Performance Scale1
Full Scale194<1
Verbal Comprehension Index93132
Perceptual Reasoning Index20.4<1
Working Memory Index418<1
Processing Speed Index8131

At age 12, she became increasingly withdrawn and developed decreased appetite and energy. Her primary physician diagnosed depression and prescribed low-dose fluoxetine. Two weeks later, she developed manic symptoms including social disinhibition (making inappropriate phone calls and social media comments), hyposomnia, and obsessive-compulsive behaviors. Urgent psychiatry consultation was obtained and she was diagnosed with bipolar disorder.

She had no history of seizures; however, an electroencephalogram (EEG) was ordered by her primary physician because of a family history of epilepsy. This revealed a 2 to 4 Hz generalized epileptiform disturbance, predominantly bifrontal, accentuated by hyperventilation and sleep, with no clinical correlation. There was intermittent slowing of background in the theta range. Subsequent prolonged video EEG recording again noted brief generalized epileptiform disturbances in the awake and sleep states with no clinical correlation. Her father had been diagnosed with primary generalized epilepsy and had a similar EEG. He is a cognitively normal individual whose seizures are well-controlled on anticonvulsants. Her non-consanguineous parents were of northern European descent.

Physical examination revealed a withdrawn and anxious female. She did not initiate conversation and showed poor eye contact. She would easily become emotional but without facial expression. She had limited insight into her state. Her speech lacked prosody. Growth parameters included: weight 53kg (75th centile), height 153.9cm (>10th centile), and head circumference 54.7cm (50th centile). Her hands and feet were cold and measured 16cm (3%) and 22cm (10%) respectively.

Neurological examination revealed bradykinesia with hypomimia. Her posture was stooped with mild kyphosis. Cranial nerve exam was normal. Positive glabellar tap and palmar grasps were present. Tone was increased, especially in the lower extremities and right arm. There was no dystonia. Deep tendon reflexes were brisk throughout (3+) and plantar responses were flexor. Sensory and coordination testing were normal. Gait was narrow based with short steps. She was unable to perform tandem gait, although she understood the command. She did not freeze and showed no difficulty turning. No tremor or postural instability was seen.

A wide differential was considered and investigated (Table 2). Cerebral spinal fluid 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels were mild-to-moderately low (5-HIAA 39 μmol/L [normal: 40–120 μmol/L], HVA 92 μmol/L [normal: 167–583 μmol/L]; Medical Neurogenetics, Atlanta, GA, USA). Brain magnetic resonance imaging and magnetic resonance spectroscopy were repeatedly normal.

Table 2. Investigations performed before MECP2 testing
Diagnostic tests performedTest purpose
  1. ANA, antinucleotide antibody; dsDNA, double stranded DNA; TSH, thyroid stimulating hormone; fT4/T3, free T4/T3; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; MRS, magnetic resonance spectroscopy.

SerumAmmonia, liver enzymes, lactate, ceruloplasmin, homocysteine, isoectric focusing for transferring, ANA, dsDNA, biotinidase, TSH, fT4, fT3x, chitotriosiadase
CSFGlucose, protein, amino acids, neurotransmitters, lactate
UrineOrganic acids, 24 urine for copper, porphobilinogen, sialic acid
ImagingMRI, MRA, MRS brain (repeated three times)
Antibody testingAntithyroid peroxidase
Leukocyte enzyme studiesBeta-galatocerebrocidase activity, beta-hexosaminidase activity
Muscle biopsy for histology and electron microscopy 
Chromosomal microarray 
Abdominal ultrasound, ophthalmological exam 

A trial of levo-dopa/carbidopa (100/25mg) did not improve her symptoms. Treatment with quetiapine partially controlled her psychiatric symptoms.

Our patient continued to exhibit progressive cognitive deterioration. Repeat neurocognitive testing at age 14 revealed further cognitive decline (Table 1). During the last 12 months of follow-up, her intelligence and behavior has stabilized.

She required repeated psychiatric admissions for mood disorder. She recently developed nocturnal urinary incontinence, increasingly poor personal hygiene (she no longer cared about her appearance and would not wash her hair or brush her teeth without parental instruction), and language deterioration (confabulation and improper sentence structure).

Based on the emerging clinical features and the negative work-up for many neurodegenerative disorders, an MECP2 gene analysis was performed, revealing a missense mutation (c.419C>T; p.Ala140Val). Her mother did not have this mutation. X chromosome inactivation pattern was normal based on analysis of a polymorphic region on the X chromosome using methylation-sensitive enzymes on DNA extracted from lymphocytes.


  1. Top of page
  2. Abstract
  3. Discussion
  4. References

This is the first female reported with the A140V MECP2 mutation who presents with late onset cognitive regression, parkinsonian features and severe psychiatric symptoms. This report further expands the MECP2 phenotype and emphasizes the need to consider MECP2 sequencing in females with non-classic RTT phenotypes, particularly those with intellectual disability and neuropsychiatric features.

Over 200 mutations have been identified in the MECP2 gene to date.[6] Our patient's MECP2 missense mutation (c.419C>T; p.Ala140Val) accounts for 0.6% of all MECP2 mutations and, to our knowledge, has not been reported previously in an individual with classic or variant RTT.

Even though our patient does not have atypical or typical RTT, it is interesting to note overlapping features. She met three of the four main criteria for atypical RTT:[7] cognitive regression and a decline in activities of daily living skills; loss of speech syntactic clarity; and increasingly abnormal gait pattern (beginning at 12y). Her regression was followed by stabilization, albeit at a lower level of function, 5 years later. She lacked stereotypic hand movements, however, and demonstrated an inability to use her hands purposefully.

Our patient also met four of five supportive criteria, including impaired sleep pattern, abnormal muscle tone, mild kyphosis and small, cold hands.

She showed clinical features observed in patients with classic RTT including parkinsonian features (observed with advancing age) and low levels of cerebral spinal fluid HVA and 5-HIAA.[8, 9]

For a female with an MECP2 mutation, the reported age of regression in our case (9y) is much later than most reported for classic and atypical RTT.[10, 11] A recent paper reports a late truncating MECP2 mutation in a female who at age 12, developed psychomotor and language regression followed by epilepsy.[12] In the cohort of 53 individuals described by Charman et al., the mean age of regression was 16 (SD 8mo) with 2 out of 53 having a regression age of 36 months or more.[10] In a larger study using the Australian and International Rett Syndrome databases, the mean age of regression was 19 years 4 months (range 3mo–4y).[11]

Our patient's clinical symptoms of parkinsonism, pyramidal signs, intellectual disability, and neuropsychiatric symptoms, closely resembles PPM-X. This was first described in a three-generation family of six affected males with moderate intellectual disability, pyramidal signs and parkinsonism (stooped posture, tremor, shuffling gait). Four of these males had a propensity for recurrent episodes of mania and depression.[5] All had some degree of macro-orchidism. Some developmental or cognitive delay was noted in the first few years of life. One had epilepsy as a toddler; none had dysmorphic features or microcephaly. The obligate carrier females had below average intelligence but were able to complete schooling. None of the females had neuropsychiatric symptoms or neurological findings on examination. Linkage analysis mapped this disorder to Xq28. Further analysis of this family revealed the A140V MECP2 mutation.[13]

This same mutation had been previously described sporadically in males with intellectual disability,[4] as well as another well-documented family with intellectual disability plus pyramidal signs and parkinsonian symptoms without neuropsychiatric features.[14, 15] This was the only family with symptomatic carrier females.[14, 15] The mother had mild intellectual disability but the daughter had both psychomotor and speech delay and performed poorly in elementary school. In addition to mild intellectual disability, she had micrognathia, genu valgum, pes planus, severe myopia, mild distal limb atrophy, mild spastic gait, brisk deep tendon reflexes, and a postural tremor. Once again, the affected males had severe intellectual disability, plus parkinsonian features (bradykinesia and resting tremor), spasticity, and distal leg atrophy.

A third three-generation family with this mutation has been described. The five affected males had varying degrees of intellectual disability noted in early childhood, including one brother with severe mood instability and another with mild dysmorphisms. The carrier females in this family were asymptomatic.[16]

Like our patient, the females in all three families had a random pattern of X chromosome inactivation.

MECP2 has two functional domains: the methyl-CpG binding domain and the transcription repressor domain. The A140V mutation is a recurrent missense mutation that substitutes an alanine for valine in the methyl binding domain. It has not been described in classic RTT. The mutation shortens the alpha helix domain of the methyl CpG binding domain but does not appear to affect methyl binding function. Instead, it seems to disrupt binding of MECP2 to ATRX, a protein associated with intellectual disability.[17]

The mouse model of the A140V mutation does not demonstrate the clinical abnormalities produced in other more classic RTT mouse models (e.g. seizures, breathing abnormalities). However, findings in the A140V mouse model include an increase in cell packing density as well as decreased dendritic branching complexity of cortical pyramidal neurons,[18] similar to that described in classic RTT neuropathology.[19]

Features of classic RTT such as abnormal breathing patterns, stereotypic hand movements, and seizures are absent in this patient, as has been reported in others with the A140V mutation. Whether the epochs of epileptiform activity are genetically inherited through the father or represent another feature of the patient's syndrome is still unknown. Epilepsy has not been frequently described in the identified kindreds. The patient did have the same phenotype described in the severely affected males including parkinsonian features, pyramidal signs[5, 14] and manic-depressive psychosis.[5] The severity of her phenotype cannot be ascribed to skewed X chromosome inactivation.


  1. Top of page
  2. Abstract
  3. Discussion
  4. References