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1 NUBPL Mitochondrial Disease: New Patients and Review of the Genetic Supplementary material J Med Genet NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum SUPPLEMENTARY DATA Detailed clinical descriptions for new patients with NUBPL disease Pedigree charts and brain MRIs for new NUBPL patients are presented in Figure 1. Summaries of new patients, along with previously published NUBPL cases, are presented in Tables 1 (clinical findings) and 2 (genetic findings). Below are detailed clinical descriptions for all five new patients presented in this study. Family 1, Patient 1A Patient 1A is a 19 year-old female, of German descent, who presented with ataxia, developmental delay, and cerebellar hypoplasia. She was born to a 20-year-old G1, P0-1 mother following a normal pregnancy. An amniocentesis was obtained because of prenatal testing suggestive of an increased risk for Down syndrome. Consanguinity was denied. The family history was significant for essential tremor in her father who had an otherwise unremarkable, neurological examination and the paternal great grandmother had isolated hand tremors. A vaginal delivery at 41 weeks gestation was complicated by a nuchal cord. Her birth weight was 3.62 kg (80th percentile), length was 53.34 cm (>90th percentile) and head circumference was 32.5 cm (20th percentile). Apgar scores were 5 and 9 at one and five minutes, respectively, and she received supplemental oxygen treatment during the resuscitation. At 3 months of age, she started having tremulousness, increased rigidity, and poor head control. Electroencephalography (EEG) and video-EEG studies were normal. Plasma amino acids, urine organic acids, lysosomal enzyme panel, peroxisomal studies and mitochondrial DNA analysis were normal. At 9 months she developed an episode of rolling back of her eyes, associated with raising and extending her arms backwards in a stiff position. Brain MRIs, obtained at 9 months and 11 months of age (data not shown), showed diffuse T2 prolongation throughout the cerebellar hemispheres with irregular enhancement within the cerebellum with 1 Kimonis V, et al. J Med Genet 2020;0:1–12. doi: 10.1136/jmedgenet-2020-106846 Supplementary material J Med Genet normal white matter and normal supratentorial appearance. The diagnosis initially considered was acute disseminated encephalomyelitis (ADEM). A cerebellar biopsy obtained at one year of age revealed markedly abnormal foliar architecture with large and irregularly distributed Purkinje neurons and Bergmann gliosis in the molecular layer. The internal granular layer showed a marked decrease in the number of cells with the remaining cells undergoing karyorrhexis. She had significant problems with her balance, and had irregular eye and ataxic hand movements and head bobbing. She started rolling from back to front and babbling at 1 year, stood independently and said her first word at 30 months, walked at 4 years with a wide based gait, and was toilet trained at 8 years. She was treated with carnitine and coenzyme Q10 for presumed mitochondrial dysfunction at age 6 years. The parents reported no significant differences, however they noted that her nystagmus and hand ataxia were slightly improved following treatment. At 6 years of age, a repeat brain MRI showed severe global prominence of the sulci in the cerebella, progressive changes with diffuse hypoplasia/atrophy and absent vermis. The cerebellar peduncle was slightly elongated with a mild increase in depth of the interpeduncular fossa. Comparisons with previous MRIs demonstrated that most of the cerebellar white matter had been lost with stable diffuse atrophy. The pons was mildly hypoplastic. The fourth ventricle was enlarged, had an unusual shape, and communicated with a large cisterna magnum. A repeat brain MRI at 16 years (Figure 1B) showed progressive cerebellar changes. Genetic/metabolic testing revealed normal results for a SNP-based copy number variant analysis, MECP2 sequencing for Rett syndrome, low density lipoprotein receptor testing, a comprehensive ataxia sequencing panel, normal metabolic testing including 7- dehydrocholesterol, and transferrin isoelectric focusing for congenital disorders of glycosylation. At 14 years of age, WES revealed a maternally inherited c.311T>C [p.L104P] variant in exon 4 of the NUBPL gene and a paternally inherited c.815-27T>C branch point variant located in the intron 9 splicing site. A muscle biopsy was arranged subsequently and mitochondrial respiratory chain complexes I-IV analysis of quadriceps muscle was normal. However, enzymatic testing revealed increased citrate synthase activity suggestive of mitochondrial proliferation. 2 Kimonis V, et al. J Med Genet 2020;0:1–12. doi: 10.1136/jmedgenet-2020-106846 Supplementary material J Med Genet Currently, she attends high school and is in special classes in the 10th grade. She does not express understanding of colors, shapes, numbers, and letters, however is able to speak using five-word sentences. She drags her feet when she walks, and her ataxia is severe. Family 1, Patient 1B Patient 1B is a 9 year old female of German descent. She is the full sibling of patient 1A. Similar to her sister, she presented with ataxia, developmental delay, and cerebellar hypoplasia. However, her clinical features are milder. She was born to a 31-year-old G3, P2-3 mother at term via vaginal delivery. Her birth weight was 4.2 kg (95th percentile) and her length was 54.6 cm (95th percentile). She fixed on her parent’s face and smiled at 6 to 8 weeks of age. At 3 months of age, she developed nystagmus and started side-to-side head shaking especially when she was tired. A neurological evaluation at 10 months revealed truncal hypotonia, horizontal nystagmus, mild tremor on reaching out for objects and hyperreflexia in the arms and legs. Her EEG was normal. She was suspected to have spinocerebellar ataxia or a mitochondrial dysfunction, and was started empirically on carnitine and coenzyme Q10 at one year of age. An MRI of the brain at 1 year of age (data not shown) showed diffuse increase in T2 signaling and mild diffuse hypoplasia of the cerebellum. The cerebellar peduncles and pons were preserved. The fourth ventricle was mildly prominent. Sanger sequencing revealed that she also had inherited the NUBPL c.311T>C [p.L104P] variant in exon 4 from her mother and the c.815-27T>C branch point variant located in intron 9 from her father. She reached for objects at 3 months, rolled at 5 months, sat at 15 months, walked at 24 months with a walker, walked independently at 4 years, and started running and saying “mom” and “dad” at 5 years. She is currently attending normal classes, is able to run without support and is making significant progress. Family 2, Patient 2 Patient 2 is a 6-year old female of English/Scottish descent who presented with ataxia, developmental delay, and cerebellar abnormalities. She was born to a 33 year-old G1 P0-1 mother by vaginal delivery. Consanguinity was denied. The family history was significant for two second cousins with autism. There are no other neurological problems reported in the family. 3 Kimonis V, et al. J Med Genet 2020;0:1–12. doi: 10.1136/jmedgenet-2020-106846 Supplementary material J Med Genet Pregnancy was complicated by a decrease in fetal movement, and labor was induced at 39 weeks for preeclampsia and fetal bradycardia. Her birth weight was 2.79 kg (16th percentile), her length was 47 cm (12th percentile), and her head circumference was undocumented but reported to be small. Apgar scores are unknown, but she was described as being vigorous after delivery and the neonatal course was only complicated by mild jaundice. She was able to crawl at 6-8 months and stand without support at one year of age. However, at the age of 13 months her parents noticed rapid developmental regression. Over time, she was no longer able to stand and her crawling became clumsy. A brain MRI obtained at age 2 years (data not shown) showed symmetric cerebellar volume loss and relative sparing of the cerebellar white matter. Arterial spin labelling revealed increased blood flow within the cerebellar peduncles. The feeding arteries of the cerebellum were enlarged and tortuous. Short, long and intermediate MR spectroscopy demonstrated a fairly large lactate peak and decreased NAA/creatinine ratio suggestive of a metabolic disorder. Based on her brain MRI findings, infantile neuroaxonal dystrophy (INAD, MIM 256600) was also considered; however, genetic testing for variants in the PLA2G6 gene was negative. A further brain MRI at age 3 years showed interval progression of non-enhancing largely symmetric signal abnormality of the bilateral cerebellar hemispheres with associated marginal restricted diffusion and cerebellar atrophy (Figure 1B). Clinical trio WES at age 3 years revealed she was compound heterozygous for maternally inherited c.815-27T>C and c.166G>A variants [p.G56R], and a paternally inherited c.693+1G>A variant. This combination was previously reported by Kevelam et al. (2013)710. Analysis of skin fibroblasts revealed normal function of electron transport chain complexes. She was subsequently treated with a mitochondrial cocktail including coenzyme Q10, carnitine, vitamins B complex, C, E, and alpha lipoic acid. She was later able to walk with a wide-based gait at 4 years and continues to make developmental progress. At 5 years of age, she was also enrolled in the EPI-743 (vatiquinone; Edison Pharmaceuticals) drug trial. EPI-743 is a small molecule designed to treat patients with mitochondrial respiratory chain disorders by targeting NADPH quinone oxidoreductase (NQO1). By parental report she has had subsequent improvement of her gross motor development. She currently has normal cognition and language with the ability to speak 3-4 word sentences with poor articulation, and is able to feed herself, scribble, and help herself get dressed. 4 Kimonis V, et al. J Med Genet 2020;0:1–12. doi: 10.1136/jmedgenet-2020-106846 Supplementary material J Med Genet Family 3, Patient 3 Patient 3 is a 23-year old male of European descent with five healthy half-siblings (three paternal sisters, one maternal sister, and a maternal brother) and an unremarkable family history.
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