Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy

Beerepoot, Shanice; Wolf, Nicole I.; Wehner, Katharina; Bender, Benjamín; Knaap, Marjo S. van der; Krägeloh‐Mann, Ingeborg; Groeschel, Samuel

doi:10.1016/j.ejpn.2022.01.020

Cited by 10 publications

(12 citation statements)

References 33 publications

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“…Thus, we could substantiate our earlier findings that in late‐infantile MLD MRI abnormalities gradually evolve after symptom onset while in juvenile MLD MRI abnormalities are already present at symptom onset, in a larger cohort and describe early signs in more detail 14 . Part of the present cohort was previously published 4,6,7,14–16,20,25–32 . Fumagalli et al.…”

Section: Discussionsupporting

confidence: 90%

“…These three early-juvenile outliers might therefore be considered as borderline lateinfantile patients, because of their unusually early age at onset, PNS dominant phenotype, and mild MRI abnormalities. 25 The variation in time before onset as well as the relatively low number of pre-symptomatic patients did not allow us to make statements about typical characteristics of pre-symptomatic MRIs. In spite of these limitations, the scans in pre-symptomatic patients certainly confirmed that in early-onset MLD the largest proportion of the MLD MRI score can be attributed to affected parietooccipital WM, whereas in late-onset patients there is a frontal predominance.…”

Section: Discussionmentioning

confidence: 96%

“…This is even more so when late-infantile patients present with strabismus or severe sensorimotor polyneuropathy, sometimes manifesting after mild viral infections and temporarily improving with immunomodulatory therapy. 25,34,35 Still, these initially mild MRIs may rapidly change into severely abnormal MRIs. The fast MRI deterioration corroborates earlier findings of Beerepoot et al that those patients have high blood neurofilament light levels indicative for already present massive neuroaxonal damage.…”

Section: Discussionmentioning

confidence: 99%

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Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Schoenmakers

Beerepoot

Krägeloh‐Mann

et al. 2022

Ann Clin Transl Neurol

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Objectives Metachromatic leukodystrophy (MLD) has characteristic white matter (WM) changes on brain MRI, which often trigger biochemical and genetic confirmation of the diagnosis. In early or pre‐symptomatic disease stages, these typical MRI changes might be absent, hampering early diagnosis. This study aims to describe the characteristics of MRI WM abnormalities at diagnosis, related to clinical presentation. Methods We retrospectively reviewed brain MRIs of MLD patients followed in 2 centers at the time of diagnosis regarding MLD MRI score and presence of tigroid pattern. In addition, MLD subtype, symptom status, CNS/PNS phenotype, motor/cognitive/mixed phenotype, and the presence of CNS symptoms were evaluated. Results We included 104 brain MRIs from patients with late‐infantile (n = 43), early‐juvenile (n = 24), late‐juvenile (n = 20) and adult (n = 17) onset. Involvement of the corpus callosum was a characteristic early MRI sign and was present in 71% of the symptomatic late‐infantile patients, 94% of the symptomatic early‐juvenile patients and 100% of the symptomatic late‐juvenile and adult patients. Symptomatic early‐juvenile, late‐juvenile and adult patients generally had WM abnormalities on MRI suggestive of MLD. By contrast, 47% of the early‐symptomatic late‐infantile patients had no or only mild WM abnormalities on MRI, even in the presence of CNS symptoms including pyramidal signs. Interpretation Patients with late‐infantile MLD may have no or only mild, nonspecific abnormalities at brain MRI, partly suggestive of ‘delayed myelination’, even with clear clinical symptoms. This may lead to significant diagnostic delay. Knowledge of these early MRI signs (or their absence) is important for fast diagnosis.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Schoenmakers

Beerepoot

Krägeloh‐Mann

et al. 2022

Ann Clin Transl Neurol

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“…While findings from this study do further validate the most common early signs and symptoms of MLD as reported in similar studies [ 3 , 16 , 18 , 25 ], its most distinct contribution is the added color on the specific language used by caregivers to describe these symptoms. This language in combination with the common early physical and cognitive signs can prove a useful resource in recognizing the clues that should trigger a workup for MLD (Table 7 ).…”

Section: Discussionsupporting

confidence: 86%

“…This study provides detailed insights into the initial signs and symptoms of MLD in the words of the caregiver which might trigger suspicion of disease for health care providers. There are few studies that focus specifically on the language used by caregivers of children with MLD—a key information source and important clue for clinicians to address individuals’ symptoms in a timely manner [ 15 – 18 ]. These first signs and symptoms are often missed during the critical window for early therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy

Eichler

Sevin²,

Barth

et al. 2022

Orphanet J Rare Dis

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Background Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy, Libmeldy (atidarsagene autotemcel), was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes insights into the caregiver language used to describe initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis. Results Data was collected through a moderator-assisted online 60-min survey and 30-min semi-structured follow-up telephone interview with 31 MLD caregivers in the United States (n = 10), France (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 20), juvenile (n = 11) or borderline late infantile/juvenile (n = 1) MLD (one caregiver reported for 2 children leading to a sample of 32 individuals with MLD). Caregivers were asked questions related to their child’s initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms of MLD and provide added context to help elevate the index of suspicion of disease. Distinctions between caregiver descriptions of late infantile and juvenile MLD in symptom onset and disease course were also identified. Conclusions This study captures the caregiver description of the physical, behavioral, and cognitive signs of MLD prior to diagnosis. The understanding of the caregiver language at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.

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Progressive demyelinating polyneuropathy after hematopoietic cell transplantation in metachromatic leukodystrophy: a case series

Beerepoot,

Boelens,

Lindemans

et al. 2024

J Neurol

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Metachromatic leukodystrophy (MLD) is a neuro-metabolic disorder due to arylsulfatase A deficiency, causing demyelination of the central and peripheral nervous system. Hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for pre-symptomatic and early symptomatic patients by stabilizing CNS disease. This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. The patients had demyelinating polyneuropathy before HCT, performed at the ages of 2 years in the first two patients and at 14 and 23 years in the other two patients. The myeloablative conditioning regimen consisted of busulfan, fludarabine and, in one case, rituximab, with anti-thymocyte globulin, cyclosporine, steroids, and/or mycophenolate mofetil for GvHD prophylaxis. Polyneuropathy after HCT progressed parallel with tapering immunosuppression and paralleled bouts of infection and graft-versus-host disease (GvHD). Differential diagnoses included MLD progression, neurological GvHD or another (auto)inflammatory cause. Laboratory, electroneurography and pathology investigations were inconclusive. In two patients, treatment with immunomodulatory drugs led to temporary improvement, but not sustained stabilization of polyneuropathy. One patient showed recovery to pre-HCT functioning, except for a Holmes-like tremor, for which a peripheral origin cannot be excluded. One patient showed marginal response to immunosuppressive treatment and died ten months after HCT due to respiratory failure. The extensive diagnostic and therapeutic attempts highlight the challenge of characterizing and treating progressive polyneuropathy in patients with MLD shortly after HCT. We advise to consider repeat electro-neurography and possibly peripheral nerve biopsy in such patients. Nerve conduction blocks, evidence of the presence of T lymphocytes and macrophages in the neuronal and surrounding nerve tissue, and beneficial effects of immunomodulatory drugs may indicate a partially (auto)immune-mediated pathology. Polyneuropathy may cause major residual disease burden after HCT. MLD patients with progressive polyneuropathy could potentially benefit from a more intensified immunomodulatory drug regime following HCT, especially at times of immune activation.

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Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy

Cited by 10 publications

References 33 publications

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy

Progressive demyelinating polyneuropathy after hematopoietic cell transplantation in metachromatic leukodystrophy: a case series

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