A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect

Bellerose, Jenny; Neugnot-Cerioli, Mathilde; Bédard, Karine; Brunel‐Guitton, Catherine; Mitchell, Grant A.; Ospina, Luis H.; Beauchamp, Miriam H.

doi:10.1007/8904_2015_517

Cited by 10 publications

(6 citation statements)

References 24 publications

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“…For prognosis or treatment evaluation, additional quantitative measures, especially from volumetric and diffusion studies, may be helpful. 46 Although cognitive and developmental impairment is an early, frequent and, unfortunately, treatment-resistant complication, 6,47,48 the registry included only fragmentary quantitative data on cognitive abilities, which seldom seem to be formally tested. To get more precise insight into the extent and pattern of cognitive impairment and to establish outcome parameters for new treatment approaches, regular, reliable testing using standardised, age-appropriate instruments would be of great value.…”

Section: Discussionmentioning

confidence: 99%

Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: Data from the E‐HOD registry

Huemer¹,

Diodato²,

Martinelli³

et al. 2019

J of Inher Metab Disea

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Aim To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E‐HOD) international web‐based registry. Results This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E‐HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy‐five percent of pre‐clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. Conclusion Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry‐based design.

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Section: Discussionmentioning

confidence: 99%

Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: Data from the E‐HOD registry

Huemer¹,

Diodato²,

Martinelli³

et al. 2019

J of Inher Metab Disea

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“…All subjects showed psychomotor delay, with a specific fall in motor skills and relative preservation of language skills and socialization. Another study assessed nine cblC patients, aged between 23 months and 24 years; five of the nine were able to perform structured examinations including the Wechsler scales, while for the other four a questionnaire on adaptive functions was filled in by the parents. The results of the Wechsler scales showed borderline scores in three patients and a mild delay in the other two.…”

Section: Introductionmentioning

confidence: 99%

“…All nine had severe visual impairment secondary to retinopathy, maculopathy, and/or nystagmus. 12 Severe ocular abnormalities have also been reported in other studies 8 and, in their presence, it is difficult to establish to which extent they contribute to the pathogenesis of intellectual disability or if developmental delay would occur independently, in the absence of overt visual defects.…”

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confidence: 97%

Early neurodevelopmental characterization in children with cobalamin C/defect

Ricci

Martinelli

Ferrantini

et al. 2020

J of Inher Metab Disea

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Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy. Children up to the age of 4 years with a visual acuity ≥1/10 were evaluated using the Griffiths' Mental Development Scales. Eighteen children were enrolled (age range 12‐48 months). Four were diagnosed by newborn screening (NBS); in the others mean age at diagnosis was 3.5 months (range 0.3‐18 months). Eight had seizures: three in the first year, and five after the second year of life. Fourteen had brain lesions on magnetic resonance imaging (MRI). Neurovisual assessment evidenced low visual acuity (<3/10) in 4/18. NBS diagnosed patients had higher general and subquotients neurodevelopmental scores, normal brain MRI, and no epilepsy. The others showed a progressive reduction of the developmental quotient with age and language impairment, which was evident after 24 months of age. Our findings showed a progressive neurodevelopmental deterioration and a specific fall in language development after 24 months in cblC defect. The presence of brain lesions and epilepsy was associated with a worst neurodevelopmental outcome. NBS, avoiding major disease‐related events and allowing an earlier treatment initiation, appeared to have a protective effect on the development of brain lesions and to promote a more favorable neurodevelopment.

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“…Following P‐OHCbl‐DI, nystagmus disappeared in cblC patients 1 and 2 and visual behavior significantly improved in cblC patient 3 with no sign of ocular disease progression at age 3 years. Compared to previous studies (Table ), most of the EO cblC patients, usually harboring a homozygous c.271dupA (p.Arg91fs), with high initial tHcy (>60 μmol/L) or high homocystine (>30 μmol/L) levels and treated at onset with low P‐OHCbl dose, have prominent developmental delay, autistic features, pigmentary retinitis, optic atrophy, marked MRI abnormalities (ventriculomegaly, WM atrophy) and persistent moderately elevated plasma tHcy levels . Importantly, homozygous c.271dupA patients with, at onset, low plasma tHcy (<60 μmol/L) or homocystine (< 30 μmol/L), may have a better prognosis …”

Section: Discussionmentioning

confidence: 80%

“…Compared to previous studies (Table 1), most of the EO cblC patients, usually harboring a homozygous c.271dupA (p.Arg91fs), with high initial tHcy (>60 μmol/L) or high homocystine (>30 μmol/L) levels and treated at onset with low P-OHCbl dose, have prominent developmental delay, autistic features, pigmentary retinitis, optic atrophy, marked MRI abnormalities (ventriculomegaly, WM atrophy) and persistent moderately elevated plasma tHcy levels. [17][18][19][20][21] Importantly, homozygous c.271dupA patients with, at onset, low plasma tHcy (<60 μmol/L) or homocystine (< 30 μmol/L), may have a better prognosis. 27 Similarly, the response of HUS to higher-doses of OHCbl in two CO cblC siblings has been specified.…”

Section: Discussionmentioning

confidence: 99%

Parenteral hydroxocobalamin dose intensification in five patients with different types of early onset intracellular cobalamin defects: Clinical and biochemical responses

et al. 2019

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Intracellular cobalamin metabolism (ICM) defects can be present as autosomal recessive or X‐linked disorders. Parenteral hydroxocobalamin (P‐OHCbl) is the mainstay of therapy, but the optimal dose has not been determined. Despite early treatment, long‐term complications may develop. We have analyzed the biochemical and clinical responses in five patients with early onset of different types of ICM defects (cblC: patients 1‐3; cblA: patient 4; cblX: patient 5) following daily P‐OHCbl dose intensification (DI). In patient 4, P‐OHCbl was started at age 10 years and in patient 5 at age 5 years. OHCbl was formulated at either, 5, 25, or 50 mg/mL. P‐OHCbl was intravenously or subcutaneously (SQ) delivered, subsequently by placement of a SQ injection port except in patient 4. In all patients, homocysteine and methylmalonic acid levels, demonstrated an excellent response to various P‐OHCbl doses. After age 36 months, patients 1‐3 had a close to normal neurological examination with lower range developmental quotient. In patient 3, moderate visual impairment was present. Patient 4, at age 10 years, had normal renal, visual and cognitive function. In cblX patient 5, epilepsy was better controlled. In conclusion, P‐OHCbl‐DI caused an excellent control of metabolites in all patients. In the three cblC patients, comparison with patients, usually harboring identical genotype and similar metabolic profile, was suggestive of a positive effect, in favor of clinical efficacy. With P‐OHCbl‐DI, CblA patient has been placed into a lower risk to develop renal and optic impairment. In cblX patient, lower P‐OHCbl doses were administrated to improve tolerability.

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A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect

Cited by 10 publications

References 24 publications

Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: Data from the E‐HOD registry

Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: Data from the E‐HOD registry

Early neurodevelopmental characterization in children with cobalamin C/defect

Parenteral hydroxocobalamin dose intensification in five patients with different types of early onset intracellular cobalamin defects: Clinical and biochemical responses

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