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. 2019 Jun 11;14(1):136.
doi: 10.1186/s13023-019-1113-6.

Phenotypic variation between siblings with Metachromatic Leukodystrophy

Saskia Elgün  1 , Jakob Waibel  1 , Christiane Kehrer  1 , Diane van Rappard  2 , Judith Böhringer  1 , Stefanie Beck-Wödl  3 , Jennifer Just  4 , Ludger Schöls  4   5 , Nicole Wolf  2 , Ingeborg Krägeloh-Mann  1 , Samuel Groeschel  6
Affiliations

Phenotypic variation between siblings with Metachromatic Leukodystrophy

Saskia Elgün et al. Orphanet J Rare Dis. .

Abstract

Background: Metachromatic Leukodystrophy (MLD) is a rare autosomal-recessive lysosomal storage disorder caused by mutations in the ARSA gene. While interventional trials often use untreated siblings as controls, the genotype-phenotype correlation is only partly understood, and the variability of the clinical course between siblings is unclear with some evidence for a discrepant clinical course in juvenile patients. The aim of this study was to systematically investigate the phenotypic variation in MLD siblings in comparison to the variability in a larger MLD cohort and to case reports published in literature.

Results: Detailed clinical information was available from 12 sibling-pairs (3 late-infantile, 9 juvenile) and 61 single patients (29 late-infantile, 32 juvenile). Variability of age at onset was similar between the siblings and randomly chosen pairs of the remaining cohort (no statistically different Euclidean distances). However, in children with juvenile MLD both the type of first symptoms and the dynamic of the disease were less variable between siblings compared to the general cohort. In late-infantile patients, type of first symptoms and dynamic of disease were similarly homogeneous between siblings and the whole MLD cohort. Thirteen published case reports of families with affected siblings with MLD are presented with similar findings.

Conclusions: In a systematic analysis of phenotypic variation in families with MLD, siblings with the late-infantile form showed a similar variability as unrelated pairs of children with late-infantile MLD, whereas siblings with juvenile MLD showed a more homogeneous phenotype regarding type of first symptoms and disease evolution in comparison to unrelated children with juvenile MLD, but not regarding their age at onset. These results are highly relevant with respect to the evaluation of treatment effects and for counseling of families with affected siblings.

Keywords: Genetics; Genotype; Metachromatic leukodystrophy; Natural course; Siblings.

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Conflict of interest statement

S.G. reports an institutional research grant from Shire plc, outside of the submitted work, and serves as co-investigator and advisor in a multicentre enzyme replacement trial sponsored by Shire plc, but receives no personal payment related to this role.

Figures

Fig. 1
Fig. 1
Age at onset of the cohort (late-infantile / juvenile). Box plots indicate distribution of age at onset for non-related children with MLD. Siblings are marked in red, with lines connecting pairs of siblings
Fig. 2
Fig. 2
Disease progression (of gross motor function). Progression of gross motor function (GMFC-MLD levels 1 to 6) of children with late-infantile (left) and juvenile (right) MLD; box plots shows distribution of non-related children with MLD within each level, siblings are marked by colored lines; note: GMFC-MLD is only applicable after the age of 18 months (=90th percentile of walking) [3]
Fig. 3
Fig. 3
T2-weighted MRI of sibling pairs in early disease stage. MRI of sibling pairs in early disease stage (at diagnosis) with the respective MRI score below illustrating the similarity in distribution of white matter changes between siblings. Axial slices of T2-weighted sequences were selected
Fig. 4
Fig. 4
Genotype – Age at onset. Variability of age at symptom onset between siblings and non-related children, carrying the same genotype, in two most common genotypes
See this image and copyright information in PMC

References

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