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Multicenter Study
. 2024 Apr;11(4):883-898.
doi: 10.1002/acn3.52002. Epub 2024 Jan 23.

Neurological outcome in long-chain hydroxy fatty acid oxidation disorders

Ulrike Mütze  1 , Alina Ottenberger  1 , Florian Gleich  1 , Esther M Maier  2 , Martin Lindner  3 , Ralf A Husain  4 , Katja Palm  5 , Skadi Beblo  6 , Peter Freisinger  7 , René Santer  8 , Eva Thimm  9 , Stephan Vom Dahl  10 , Natalie Weinhold  11 , Karina Grohmann-Held  12 , Claudia Haase  13 , Julia B Hennermann  14 , Alexandra Hörbe-Blindt  15 , Clemens Kamrath  16 , Iris Marquardt  17 , Thorsten Marquardt  18 , Robert Behne  1 , Dorothea Haas  1 , Ute Spiekerkoetter  19 , Georg F Hoffmann  1 , Sven F Garbade  1 , Sarah C Grünert  19 , Stefan Kölker  1
Affiliations
Multicenter Study

Neurological outcome in long-chain hydroxy fatty acid oxidation disorders

Ulrike Mütze et al. Ann Clin Transl Neurol. 2024 Apr.

Abstract

Objective: This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide.

Methods: German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes.

Results: Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved.

Interpretation: While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.

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Conflict of interest statement

SK and GFH received research grants from the Dietmar Hopp Foundation, St. Leon‐Rot, Germany. All other authors have nothing to report.

Figures

Figure 1
Figure 1
Onset and frequency of first metabolic decompensation and disease‐specific symptoms in LCHAD and MTP deficiency identified by NBS. Kaplan–Meier curves. (A) first metabolic decompensation, (B) myopathy, (C) cardiomyopathy, (D) hepatopathy, (E) retinopathy, and (F) neuropathy. Neuropathy occurred later in LCHAD than in MTP deficiency (p = 0.0447). No further differences were observed.
Figure 2
Figure 2
Mean individual annual rates of decompensations (A) and hospitalizations (B) in LCHAD and MTP deficiency identified by NBS. Hospitalization rate was highest in the first year for LCHAD and MTP deficiency (2.04), while the overall decompensation rate was highest in the fourth year (0.77). During the second year of life, individuals with MTPD were hospitalized more frequently (2.39 times per year) than those with LCHADD (1.04 times; p = 0.0010), while hospitalization did not differ for other age groups. Annual hospitalization rate of the German pediatric reference population is depicted in gray.
Figure 3
Figure 3
Dietary treatment in LCHAD and MTP deficiency identified by NBS. (A) Overall achievement of dietary goals, (B) Achievement of the different dietary goals. Calculated for the first 10 years of life based on consensus group recommendations and national guidelines. Therapy components were the restriction of (1) long‐chain triglycerides intake and (2) fasting time and substitution of (3) medium‐chain triglycerides, and (4) essential fatty acids. The data were collected by analyzing the medical and dietary records annually for each participant retrospectively.
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