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Genetic leukodystrophies (gLD), encompassing inherited disorders affecting cerebral white matter, are a heterogeneous group of diseases.1 While they classically first manifest in childhood, adolescent and adult-onset forms are increasingly recognised.2 3 Different pathological mechanisms produce white matter abnormalities (WMAs) depending on the affected gene.1 Hypomyelinating gLD (H-gLD) share the common histological feature of decreased myelin formation in the brain, in contrast to demyelinating gLD (loss of previously formed myelin), dysmyelinating gLD (deposition of structurally abnormal myelin) and myelinolytic disorders (vacuolisations disrupting myelin integrity).1
MRI characteristics help discriminate hypomyelination from other WMAs. In H-gLD, WMAs are widespread, mildly hyperintense on T2/fluid attenuation inversion recovery and associated with diffuse T1 hyperintense, isointense or mildly hypointense signal relative to the grey matter.4 In other gLD, WMAs can be focal or confluent, often with regional predominance, and prominent T2 hyperintensity with marked T1 hypointensity.2 4 H-gLD typically present in the neonatal period with axial hypotonia, followed by spastic paraparesis and delayed motor development in early childhood.2 4 Nystagmus, cerebellar ataxia, extrapyramidal syndrome and cognitive impairment can later develop.3 4 Depending on the gene defect, extraneurological signs have been described.4 Adolescent/adult-onset H-gLD are exceptionally reported.2 We report findings in three unrelated patients with late-onset neurological symptoms and hypomyelinating features on brain MRI.
Brain MRI of our patients are shown in figure 1, all showing diffuse WMAs suggestive of isolated hypomyelination. Candidate variants detected by next-generation sequencing (NGS), clinical and electrophysiological features are summarised in online supplementary table 1. The genes included in the panels are listed in online supplementary table 2. Genetic methodology, molecular characteristics and bioinformatics prediction tools of the identified variants are summarised in online supplementary table 3.
A 24-year-old man was referred with a 9-year history of progressively worsening gait impairment. At age 15, he experienced decreased tolerance to strenuous exercise, forcing him to stop playing soccer. Since age 18, abnormal gait and increasingly frequent falls were noted. There were no behavioural changes or cognitive decline. On physical examination, Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) were 24/30 and 15/18, respectively. The patient was apathetic. Gait was spastic, paretic and mildly ataxic. Visual (VEP), somatosensory (SSEP) and brainstem auditory evoked potentials (BAEP) were severely altered. NGS detected a previously unreported heterozygous variant in the TUBB4A gene (c.937G>T;p.Val313Leu). At last follow-up, he continued to worsen, with bilateral support needed for ambulation and apathy.
A 37-year-old woman was brought by her parents for a 3-year history of progressive behavioural changes and cognitive decline. Medical history was significant for primary amenorrhoea, moderate myopia in both eyes and type 1 diabetes mellitus. Parents noted a lack of insight, progressive difficulties in accomplishing simple tasks, mild memory impairment and aggressive behaviour. MMSE and FAB were 22/30 and 11/18, respectively. The patient exhibited disinhibition and irritability. The rest of the examination was normal. BAEP were mildly altered; VEP and SSEP were normal. NGS found two heterozygous mutations of the POLR3A gene (c.3014G>A (p.Arg1005His)/maternal, c.3858C>A (p.His1286Gln)/paternal). At last follow-up, the patient exhibited stable behavioural abnormalities and remained partially dependent for daily activities.
A 41-year-old woman was evaluated for progressive gait and cognitive impairment. Medical history was notable for treatment-resistant bipolar disorder since age 16, with recurrent suicidal attempts. Her mother and maternal grandmother (both deceased) exhibited prominent psychiatric symptoms and dementia. At age 31, she developed gait imbalance, necessitating use of a cane. Cognitive decline became evident in her mid-30s and associated with severe depression. Physical examination demonstrated MMSE 22/30, FAB 8/18, spastic/ataxic gait and bilateral upper extremity ataxia. VEP were mildly altered. NGS detected a previously unreported heterozygous mutation in the HSPD1 gene (c.1625C>G (p.Ala542Gly)). At last follow-up, physical examination was stable. Patient still required unilateral support for ambulation and was partially dependent to accomplish household tasks.
There are limited published data on adolescent/adult-onset H-gLD, with most cases associated to POLR3A/POLR3B, rarely to PLP-1 and other genes.2 Our report highlights that H-gLD related to rare gene defects can initially manifest in adolescence and adulthood with unusual presentations, expanding their phenotypic spectrum. In comparison with paediatric forms, symptoms are milder, and imaging lacks additional gene-specific features other than findings suggesting diffuse hypomyelination, accounting for the difficulty and delay in establishing diagnosis (figure 1). For example, a single allele mutation in the TUBB4A gene, classically known to cause hypomyelination with basal ganglia and cerebellar atrophy (H-ABC) (OMIM 612438), manifests early in life with developmental delay, dystonia, choreoathetosis, ataxia, spastic tetraplegia, and neostriatal and cerebellar atrophy along with hypomyelination on MRI.5 Mutations of the POLR3A gene typically manifests before the age of 10 with hypomyelination, hypogonadotropic hypogonadism and hypodontia, the so-called 4H- syndrome (OMIM607694).3 T2 hypointensity of the thalami, pallidum and optic radiations, along with diffuse hypomyelination, are often observed.4 A single-allele mutation in the HSPD1 gene causes an uncomplicated form of autosomal dominant hereditary spastic paraplegia, SPG13 (OMIM605280), whereas biallelic mutations cause a severe infantile-onset H-gLD, HLD4 (OMIM612233). Patient C seems to have an overlapping presentation between SPG13 and HLD4 phenotypes, and involvement of an undetected second mutation cannot be ruled out.
Our observation is limited by the lack of parental testing in two patients, precluding distinguishing hereditary transmission versus de novo occurrence of the identified mutations. Future reports of these unreported variants would be helpful to establish their pathogenicity.
The reason why some patients have a milder later-onset disease is unclear. The quantity of preserved myelin is proportional to the increase in T1 signal intensity.4 All our patients had diffuse white matter T1 hyperintensity, suggesting that more myelin may be initially formed in adolescent/adult-onset cases. Regions of mild T1 hypointensity seen in two patients suggest that prominent decrease in myelin formation may be regional, leading to specific clinical features.
Diagnosing gLD is challenging and limited in practice by the lack of an established scheme for using genetic testing and payer coverage. Certain MRI features (ie, diffuse and widespread WMAs in the absence of T1 hypointensity) can suggest H-gLD.4 Recognition of hypomyelination can focus genetic testing to facilitate making the correct diagnosis.4
Contributors GM and YN contributed equally in the conception of the manuscript, the acquisition of the data and drafting of a significant portion of the manuscript, tables and figures. JAC contributed in drafting and editing a significant portion of the manuscript. SS contributed in the analysis of the data and drafting a significant portion of the manuscript and tables. All authors approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests GM received fellowship funding from the National Multiple Sclerosis Society Institutional Clinician Training Award ICT 0002 and Biogen Fellowship Grant 6873-P-FEL. SS has nothing to disclose. JAC received personal fees for consulting for Adamas, Alkermes, Convelo, EMD Serono, Novartis and Pendopharm; speaking for Mylan and Synthon; and serving as a Co-Editor of Multiple Sclerosis Journal—Experimental, Translational and Clinical. YN received speech honoraria from Actelion and Orphan Europe, and received travel funding from Actelion, Shire and Genzyme.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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