https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312865-sup-v001.htm
Methyl CpG‐binding protein 2 (MeCP2) deficiency is associated to Rett syndrome (RTT), an X‐linked neurodevelopmental disorder affecting females, accounting for 95% to 97% of typical RTT.1 The first male patient with MECP2 mutation was described in 1999, overcoming the concept of lethality of MeCP2 deficiency in males, and, later on, a number of patients with early‐onset severe encephalopathy were described.2 MECP2 is now recognized to be causative of a wide spectrum of clinical manifestations in males, including cognitive impairment, movement disorders, and epilepsy.3
Here we report on a new phenotypic presentation of MeCP2 deficiency characterized by intellectual disability, early‐onset parkinsonism, and vertical supranuclear gaze palsy (VSGP).
This 17‐year‐old male was born at term without complications from nonconsanguineous healthy parents. He was able to walk at 16 months and spoke his first words at 24 months of age. At the age of 4 years, upper limb tremor was noticed, and at the age of 8, a neuropsychological evaluation revealed a borderline intellectual functioning. At that time, karyotype, FMR1 sequencing, and single‐nucleotide polymorphism array revealed no abnormalities.
At the age of 16 years, he suffered from an acute‐onset psychomotor agitation, confabulation, and visual hallucinations. On examination, a few weeks later, he presented a catatonic state, with stupor, akinesia, waxy flexibility, mutism, staring, and catalepsy (Video 1, segment 1). He also had hypostaturism. A lorazepam trial (2 mg) rapidly resolved the catatonic state. Once catatonia resolved VSGP, intermediate‐frequency low‐amplitude postural and kinetic tremor with superimposed distal jerks and only minimal rest component, upper limb slight dystonic posturing, bradykinesia, rigidity, and anterior neck flection became evident (Video 1, segments 2–4). Finger tapping showed decrement in both rate and amplitude (Video 1, segment 3). Lower limb reflexes were brisk. A reevaluation of his cognitive function revealed moderate cognitive impairment (IQ = 40). An extensive metabolic workup, including plasma aminoacids, urinary organic acid, acylcarnitine, plasma oxysterols, lactate, pterins, and cerebrospinal fluid neurotransmitter metabolites failed to detect any specific alterations. Brain MRI and DaT‐scan were both normal. A levodopa trial was ineffective. Next‐generation sequencing panels for monogenic parkinsonisms and dystonias were inconclusive. Finally, whole‐exome sequencing detected a novel MECP2 c.503G>A (p.Arg168Gln) missense variant, inherited from his unaffected mother and predicted as pathogenic by different tools.4
Whereas MeCP2 deficiency accounts for 1.3% to 1.7% of males with cognitive impairment,3 parkinsonian features have been reported in few patients (Table 1).5, 6, 7, 8
Table 1.
Parkinsonism and associated features in male patients with MECP2 alterations
| Reference (Case No.) | Age (Years) | Parkinsonian features | Cognitive Functioning | Brisk Tendon Reflexes | Action Tremor | Other Clinical Findings | Genotype |
|---|---|---|---|---|---|---|---|
| Lindsay et al.,19965 (case 1) | 11 |
Bradykinesia, resting tremor, shuffling gait |
Moderate cognitive impairment (IQ = 49) | + |
+ |
Psychotic bipolar disorder |
c.419C>T p.Ala140Val |
| Lindsay et al.,19965 (case 2) | 39 | Resting tremor and shuffling gait | Moderate cognitive impairment | + | – |
Psychotic bipolar disorder |
c.419C>T p.Ala140Val |
| Orrico et al., 20006 (cases 1‐4) | 27 to 40 | Bradykinesia and resting tremor | Severe cognitive impairment | – | – | – |
c.419C>T p.Ala140Val |
| Couvert et al., 20017 (cases 1‐3) | 25 to 50 | Resting tremor | Mild to moderate cognitive impairment (IQ = 50–70) | – | – | – |
c.499C>T p.Arg167Trp |
| Chahil et al., 20188 (case 1) | 16 | Bradykinesia, resting tremor, camptocormia |
Neurodevelopmental disorder |
+ | + | Autistic spectrum disorder |
c.419C>T p.Ala140Val |
| Present case | 18 | Rigidity, hypomimia, mild camptocormia, resting tremor |
Moderate cognitive impairment |
+ | + | Catatonia, psychotic features, vertical gaze palsy |
c.503G>A p.Arg168Gln |
A specific syndromic constellation encompassing psychosis, pyramidal signs, and macro‐orchidism (PPM‐X), as well as cognitive impairment, parkinsonism, and short stature, has been described in 6 males from the same family harboring the MECP2 A140V variant.9 Although MECP2 is recognized to cause rigid‐hypokinetic syndrome in Rett females in the advanced stage of the disease,10 parkinsonism with VSGP, evoking a PSP‐like phenotype,11 has not been previously reported in males with MECP2 variants. The tremor observed in this patient according to phenomenology has similarities with both essential tremor–like tremor of fragile X–associated tremor/ataxia syndrome12 and cortical reflex myoclonus observed in RTT and other conditions13; detailed electrophysiological studies are needed for proper characterization.
The C.503G>A variant is adjacent to the c.502C>T, one of the most frequent MECP2 alterations found in females with typical RTT.14
This case, expanding the phenotypic spectrum of MeCP2 deficiency, suggests that this gene may be a neglected cause of parkinsonism and intellectual disability in males, deserving to be added to the differential diagnosis of early‐onset parkinsonism in males with cognitive impairment.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique.
L.P.: 1A, 2A
S.G.: 1A, 2A
F.N.: 1B, 1C
F.M.: 1B, 1C
R.C.: 1B, 1C
V.N.: 2A, 2B
V.L.: 2A, 2B
Disclosures
Ethical Compliance Statement: We declare that the patients and/or their parents consented for video publication and provided a signed release form authorizing the offline and/or online distribution of this video material. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work.
Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: Vincenzo Leuzzi has served on scientific advisory boards for Nutricia and BioMarin.
Supporting information
Video S1. Segment 1: clinical presentation with catatonic features including facial grimaces and mutism. Segment 2: resolution of catatonic state after lorazepam trial; severe vertical gaze palsy. Segment 3: resolution of catatonic state after lorazepam trial; persistent hypomimia, postural tremor of upper limbs with occasional distal jerks, and upper limb slight dystonic posturing. On finger tapping, reduction of both amplitude and speed rate and exacerbation of distal myoclonic jerks. Segment 4: anterior neck flection, hand‐washing stereotypies, and reduced arm swing during gait.
Dr. Pollini and Dr. Galosi contributed equally to the manuscript. Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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Associated Data
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Supplementary Materials
Video S1. Segment 1: clinical presentation with catatonic features including facial grimaces and mutism. Segment 2: resolution of catatonic state after lorazepam trial; severe vertical gaze palsy. Segment 3: resolution of catatonic state after lorazepam trial; persistent hypomimia, postural tremor of upper limbs with occasional distal jerks, and upper limb slight dystonic posturing. On finger tapping, reduction of both amplitude and speed rate and exacerbation of distal myoclonic jerks. Segment 4: anterior neck flection, hand‐washing stereotypies, and reduced arm swing during gait.