Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands

被引：9

作者：

Schwantje, Marit ^{[1
,2
,3
]}

Fuchs, Sabine A. ^{[1
]}

de Boer, Lonneke ^{[4
]}

Bosch, Annet M. ^{[3
,5
]}

Cuppen, Inge ^{[6
]}

Dekkers, Eugenie ^{[7
,8
]}

Derks, Terry G. J. ^{[9
]}

Ferdinandusse, Sacha ^{[2
,3
]}

Ijlst, Lodewijk ^{[2
,3
]}

Houtkooper, Riekelt H. ^{[2
,3
]}

Maase, Rose ^{[7
,8
]}

van der Pol, W. Ludo ^{[6
]}

de Vries, Maaike C. ^{[4
]}

Verschoof-Puite, Rendelien K. ^{[10
]}

Wanders, Ronald J. A. ^{[2
,3
]}

Williams, Monique ^{[11
]}

Wijburg, Frits ^{[3
,5
]}

Visser, Gepke ^{[1
,2
,3
]}

机构：

[1] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Metab Dis, Lundlaan 6, NL-3584 EA Utrecht, Netherlands

[2] Univ Amsterdam, Lab Genet Metab Dis, Amsterdam UMC, Amsterdam, Netherlands

[3] Univ Amsterdam, Metab Inst, Amsterdam UMC, Amsterdam, Netherlands

[4] Radboud Univ Nijmegen Med Ctr, Amalia Childrens Hosp, Dept Metab Dis, Nijmegen, Netherlands

[5] Univ Amsterdam, Emma Childrens Hosp, Amsterdam UMC, Dept Metab Dis, Amsterdam, Netherlands

[6] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Neurol & Neurosurg, Utrecht, Netherlands

[7] Ctr Hlth Protect RM, Natl Inst Publ Hlth & Environm RIVM, Reference Lab Pre & Neonatal Screening, Bilthoven, Netherlands

[8] Ctr Populat Screening ED, Bilthoven, Netherlands

[9] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Dept Metab Dis, Groningen, Netherlands

[10] Natl Inst Publ Hlth & Environm, Dept Vaccine Supply & Prevent Programs, Bilthoven, Netherlands

[11] Univ Med Ctr Rotterdam, Ctr Lysosomal & Metab Dis, Dept Pediat, Erasmus MC, Rotterdam, Netherlands

来源：

JOURNAL OF INHERITED METABOLIC DISEASE | 2022年 / 45卷 / 04期

关键词：

LCHAD deficiency; LCKAT deficiency; long-chain fatty acid oxidation; mitochondrial trifunctional protein complex; MTP deficiency; newborn screening; FATTY-ACID OXIDATION; 3-HYDROXYACYL-COA DEHYDROGENASE-DEFICIENCY; BETA-OXIDATION; FOLLOW-UP; PERIPHERAL NEUROPATHY; DEFECTS; MYOGLOBINURIA; MUTATIONS;

D O I：

10.1002/jimd.12502

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid beta-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP-deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP-deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.

引用

页码：804 / 818

页数：15

共 36 条

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