Rötig Agnès, Gaignard Pauline, Barcia Giulia, Assouline Zahra, Berat Claire-Marine, Barth Magalie, Damaj Léna, Laborde Nolwenn, Abi-Warde Marie-Thérèse, Chabrol Brigitte, De Lonlay Pascale, Desguerre Isabelle, Goldenberg Alice, Gonzales Emmanuel, Jacquemin Emmanuel, Amati-Bonneau Patrizia, Bonneau Dominique, Abadie Véronique, Bonnemains Chrystèle, Broue Pierre, De Saint-Martin Anne, Durand Philippe, Fouilhoux Alain, Isidor Bertrand, Jaroussie Marianne, Jedraszak Guillaume, Maurey Hélène, Mention Karine, Odent Sylvie S, Pasquier Laurent, Rougeot-Jung Christelle, Gitiaux Cyril, Roux Charles-Joris, Boddaert Nathalie, Munnich Arnold, Schiff Manuel
From the Université Paris Cité (A.R., M.S.), Institut Imagine, Génétique des maladies mitochondriales, INSERM UMR 1163; Centre de Référence des Maladies Mitochondriales (A.R., P.G., G.B., Z.A., C.-M.B., M.B., M.-T.A.-W., P.D.L., I.D., E.G., E.J., A.D.S.-M., N.B., A.M., M.S.), AP-HP, Hôpital Necker-Enfants Malades, Paris; Service de Biochimie (P.G.), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre; Service de médecine génomique des maladies rares (G.B., Z.A.), AP-HP, Hôpital Necker-Enfants Malades, Paris; Service de Génétique (M.B., D.B.), Centre Hospitalier Universitaire; Service de génétique clinique (L.D.), Centre de Compétences Maladies Héréditaires du Métabolisme, CHU de Rennes; Unité de Gastroentérologie (N.L., P.B.), Hépatologie, Nutrition, Diabétologie et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, CHU de Toulouse; Service de Neuropédiatrie (M.-T.A.-W., A.D.S.-M.), CHU de Strasbourg; Service de Neurométabolisme pédiatrique (B.C.), CHU Timone, Marseille; Service et Centre de référence des maladies héréditaires du métabolisme (P.D.L., M.S.); Service de Neurophysiologie pédiatrique (I.D., C.G.), AP-HP, Hôpital Necker-Enfants Malades, Paris; Service de Génétique (A.G.), CHU de Rouen; Pediatric Hepatology and Pediatric Liver Transplant Unit (E.G., E.J.), AP-HP, CHU Bicêtre, Le Kremlin-Bicêtre; Laboratoire de Biochimie et Biologie Moléculaire (P.A.-B.), CHU d'Angers; Pédiatrie générale et maladies infectieuses (V.A.), AP-HP, Hôpital Necker-Enfants Malades, Paris; Service de médecine infantile (C.B.), CHU de Nancy; Service de Réanimation pédiatrique et néonatale (P.D.), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre; Centre de référence des maladies héréditaires du métabolisme (A.F.), Hospices civils de Lyon, CHU de Lyon; Service de génétique médicale (B.I.), CHU de Nantes; Service de Neurologie Pédiatrique (M.J.), AP-HP, Hôpital Robert Debré, Paris; Génétique Clinique et Oncogénétique (G.J.), CHU Amiens-Picardie; Service de Neurologie pédiatrie (H.M.), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre; Centre de référence des Maladies Héréditaires du métabolisme (K.M.), Hôpital Jeanne de Flandre, Lille; Service de Génétique Clinique (S.S.O., L.P.), CRMR anomalies du développement CLAD-Ouest, Rennes; Service de neurologie pédiatrique (C.R.-J.), Hospices civils de Lyon, CHU de Lyon; Imagerie pédiatrique (C.-J.R., N.B.), AP-HP, Hôpital Necker-Enfants Malades, Université Paris Cité; and Université Paris Cité (A.M.), Imagine Institute, INSERM UMR 1163, Paris, France.
Neurol Genet. 2024 Jul 3;10(4):e200167. doi: 10.1212/NXG.0000000000200167. eCollection 2024 Aug.
DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. -related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic variants.
The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency.
Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types.
The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.
DNA聚合酶γ亚基（POLG）缺乏可能是核编码线粒体疾病最常见的病因。据报道，相关疾病构成了从婴儿期到成年晚期一系列重叠的表型。我们回顾性分析了40例携带双等位基因致病变异儿童的自然病史。
这些患者由法国线粒体疾病协调中心（CARAMMEL）识别，这是一个关于儿童期起病的POLG缺乏的大型单中心系列研究。
观察到三种临床病程和生存模式，以主要症状类别区分：神经、肝脏和胃肠道。共有24例患者因强直阵挛性发作、肌阵挛性癫痫和癫痫持续状态需要紧急神经重症监护，这些情况偶尔由丙戊酸盐给药诱发。其他神经症状包括肌张力障碍、小脑共济失调和周围神经病变。我们报告了6例POLG缺乏患者，其多神经根神经病类似亚急性吉兰-巴雷综合征，并提供了钆增强磁共振成像证据，显示弥漫性颅神经根强化，提示这些疾病有炎症成分。出现肠神经系统受累的儿童有呕吐、胃轻瘫和慢性肠假性梗阻。他们起病年龄较晚，存活时间更长。主要表现为肝脏症状的患者起病最早，存活时间最短。在诊断前给予有局灶性意识障碍发作或无发作的患者丙戊酸盐治疗，常导致继发性肝衰竭。这些POLG缺乏症通常是致命的，死亡年龄在3个月至10岁之间，三种临床类型的生存情况有显著差异；40例儿童中有6例存活。在三种临床病程类型中未发现基因型与表型的相关性。
该研究表明60%的患者存在神经症状表现以及中枢、外周和自主神经系统受累的程度。大多数起病早且迅速致命的肝功能衰竭患者存活时间不足以出现神经症状。该研究揭示了一种新的POLG缺乏临床类型，表现为神经消化症状，生存期较长。我们还建议，对于出现不明原因的多神经根神经病、脱髓鞘性神经病和脑脊液蛋白升高的儿童，应考虑POLG缺乏症。最后，丙戊酸盐给药仍然是POLG缺乏症患者可避免死亡的一个显著原因。
