WDR45 Mutation in Atypical Rett Syndrome with Brain Iron Accumulation

This case was included in the series by Hayflick et al.,1 but is reported here in greater detail to illustrate the clinical features. The proband had no family history of neurodevelopmental or movement disorders. Her mother was induced at 36 weeks for hypertension, but there was no significant birth trauma and the early neonatal period was uneventful. She was considered developmentally normal at birth. Her head circumference was on the 60th centile, with no subsequent falloff during childhood. At 8 months, she was noted to have an immature palmar grasp. She sat unsupported at 7 months and walked at 13 months of age. At 13 months, she suffered acute pharyngitis complicated by a febrile seizure with a prolonged period of unconsciousness. She subsequently developed right‐sided weakness—she did not use her right hand and tended to fall toward the right side. Global developmental problems became increasingly apparent thereafter. By 2.5 years, she had only a few single words, would scribble but not draw, could walk upstairs only with assistance, and would not run. Her MRI scan showed a left frontal infarct. She had recurrent generalised tonic‐clonic seizures. An EEG showed bilateral and left‐sided episodes of irregular theta waves associated with sharp waves, consistent with the structural abnormality on MRI. Sodium valproate was introduced, but replaced with phenobarbitone, then carbamazepine. After 2 years of seizure freedom, antiepileptic medications were withdrawn at the age of 9, with no subsequent attacks. Her developmental disabilities remained stable through her childhood years.

She presented to adult services at age 24, with deterioration in her communication and motor skills. She no longer verbalized, but used limited signs and made noises. She could walk, managed basic self‐care, and was continent. She showed abnormal episodic agitation, crying and laughing, and had a high pain threshold. On examination, her gait was broad‐based and ataxic, and she exhibited perseverative hand movements.

An MRI scan showed diffuse atrophy, predominantly of the left temporal lobe. Her EEG showed low‐voltage β‐background activity with occasional α components and no epileptiform activity. Her karyotype was 46XX. Lactate and creatine kinase were normal. White cell and plasma enzymes were within normal limits, and very‐long‐chain fatty acids were not indicative of a peroxisomal disorder. Ceruloplasmin and serum copper were slightly raised, but were normal on repeat testing. In the pediatric neurology clinic, a diagnosis of atypical Rett syndrome was considered most likely, given her developmental delay, including gait disturbance, prominent loss of expressive language, seizures, perseverative hand movements, emotional lability, and diminished pain responses. However, molecular analysis of MECP2 for mutations (including copy number variants) performed at this stage was negative. Her phenotype was not consistent with mutations in genes associated with atypical Rett syndrome (CDKL5 and FOXG1).

Over the next 5 years, her gait became increasing unsteady and hesitant, with dystonic posturing of her arms, particularly on the right. The perseverative hand movements persisted (see Video). She also developed urinary incontinence. A repeat MRI, performed when she was 29 years old, revealed further atrophy of both cerebral hemispheres, predominantly the frontal and temporal lobes, with moderate hippocampal and midbrain atrophy. Interestingly, there was also evidence of brain iron accumulation in the basal ganglia and both cerebral peduncles (Fig. 1). This result shifted investigations to conditions of neurodegeneration with brain iron accumulation (NBIA).

Figure 1.

MRI findings. The globus pallidus is hypointense on axial T2 (A) and FLAIR sequences (C). SN on axial T1 (B) and fluid‐attenuated inversion recovery (D) shows even greater hypointensity, suggestive of high levels of iron in these structures. Uniquely in BPAN, SN shows a halo of hyperintense signal surrounding a thin linear region of hypointense signal on T1‐weighted imaging, seen here on a sagittal view (E).

The imaging findings were typical for beta‐propeller protein‐associated neurodegeneration (BPAN). The clinical phenotype of stable neurodevelopmental disability in childhood, followed by deterioration in young adulthood, was also consistent with this diagnosis.

Our patient underwent sequencing of the gene associated with BPAN (WDR45). This revealed a pathogenic mutation, c.1A>G (p.Met1Val), predicted to abolish the start codon. The mutation was de novo, occurred at a highly conserved residue across species, and was not detected in 1,000 genomes.

Discussion

Three to five percent of patients with classic and 30% to 50% with atypical Rett syndrome do not have MECP2 mutations.2 Other genes account for the phenotype in some individuals, including CDKL5 and FOXG1, but a significant proportion of individuals with Rett or atypical Rett syndrome remain genetically unexplained. Without a secure diagnosis, it is difficult to predict disease course and provide accurate genetic counseling to the family and more difficult to involve patients in therapeutic trials. In our case, the pivotal diagnostic breakthrough was repeat neuroimaging revealing brain iron accumulation. Making a diagnosis of BPAN has led us to consider levodopa as a future therapeutic intervention.

The clinical spectrum of BPAN is probably highly variable, given the proposed disease mechanisms of skewed X‐inactivation in females and mosaicism in both sexes.3, 4 Thus far, only cases with brain iron accumulation on neuroimaging have been identified, although historical imaging suggests that iron accumulation may be undetectable until the second decade.1 Among the initial cohort of 23 BPAN patients, 7 had some Rett‐like features.1 The proportion of individuals with Rett‐like phenotypes resulting from BPAN remains to be established, but investigation for evidence of NBIA on imaging and/or genetic testing for BPAN should be considered in these cases, especially where mutations in MECP2 are absent. The clinical (and genetic) similarities of BPAN with Rett (Table 1) are intriguing, and further elucidation of the metabolic pathways may provide new insights into the pathogeneses of these clinically overlapping disorders. Additionally, the case illustrates the value of information from repeat MR imaging (ideally with T2*) in cases of unexplained developmental regression and/or evolving movement disorder.

Table 1.

Comparison of the clinical features described in BPAN with the diagnostic criteria for Rett syndrome1, 2

	RETT	BPAN
Inheritance	Female predominance; X‐linked dominant, usually de novo mutation	Female predominance; X‐linked dominant, de novo mutation
Natural history	Regression followed by recovery or stabilization	Global developmental delay with regression in early adulthood
Main criteria
Hand skills	Partial or complete loss of hand skills	Not known
Language	Partial or complete loss of acquired spoken language	Limited expressive language common
Gait abnormalities	Impaired (dyspraxia) or absence of ability	Slow motor gains common and spasticity described in childhood; dystonia and parkinsonism common
Stereotypic hand movements	Hand wringing/squeezing, clapping/tapping, mouthing and rubbing/washing automatisms	Described
Supportive criteria
Breathing disturbances when awake	Described	Not known
Bruxism when awake	Described	Described
Impaired sleep pattern	Described	Described
Abnormal muscle tone	Described	Not known
Peripheral vasomotor disturbances	Described	Not known
Scoliosis/kyphosis	Described	Not known
Growth retardation	Described	Not known
Small cold hands and feet	Described	Not known
Inappropriate laughing/screaming spells	Described	Described
Diminished response to pain	Described	Described
Intense eye communication “eye pointing”	Described	Not known
Other clinical features
Seizures	Common focal, absence, atonic/tonic, generalized tonic‐clonic, myoclonic, multiple types	Common focal, absence, atonic/tonic, generalized tonic‐clonic, myoclonic, multiple types
Microcephaly	Well described	Not described
Ocular defects	Not described	Described; patchy loss of pupillary ruff, bilateral partial retinal colobomata, high myopia, astigmatism with myopia, spontaneous retinal detachment
Imaging findings	Cerebral atrophy	T2 hypointense SN and GP, T1 hyperintense “halo” in SN/cerebral peduncles; cerebral atrophy

Atypical/variant Rett requires 2 of 4 main criteria and 5 of 11 supportive criteria.

Shading highlights the known similarities between RETT and BPAN.

GP, globus pallidus.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

S.J.C.: 1A, 1B, 1C, 3A

E.M.: 1C, 3B

A.G.: 1C, 3B

H.A.: 1C, 3B

S.H.: 1C, 3B

M.A.K.: 1C, 3B

R.D.S.: 1A, 1B, 3B

Disclosures

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: S.J.C. has received support from the National Health Service (NHS) and is a Wellcome Trust Postdoctoral Clinical Research fellow, E.M is funded by Great Ormond Street Hospital Chidlren's Charity (GOSHCC) and the NBIA Disorders Association, H.A. has received support from the NHS, S.J.H. receives support from the NBIA Disorders Association, the European Commission, and Retrophin, Inc., M.A.K is an Wellcome Trust Intermediate Fellow, and receives funding from Great Ormond Street Children's Hospital Charity (GOSHCC), Gracious Heart Charity Foundation, Rosetrees Trust, the AADC Research Trust and the NBIA Disorders Association, and R.D.S. receives support from NHS and has had a travel grant from UCB.

Supporting information

A video accompanying this article is available in the supporting information here.

Video. Typical hand automatisms: Tapping, rubbing and hand‐wringing are demonstrated. Gait disturbance: The gait is wide‐based and apraxic with dystonic posturing of the arms.