Six subjects from five unrelated...

Six subjects from five unrelated families were included in the study (Fig. 1A), with four from consanguineous families. Informed consent for diagnostic and research studies was obtained for all subjects in accordance with the Declaration of Helsinki protocols and approved by local institutional review boards. Clinical features are summarized in Table 1, with brain imaging shown in Fig. 1B. Five of six subjects had an antenatal disease, associating lack of foetal movements or polyhydramnios, dysmorphic features and severe encephalopathy with marked pontocerebellar hypoplasia with a simplified gyral pattern. Subject S5 had a milder presentation characterized by mental retardation and dystonia in childhood, followed by onset of cerebellar ataxia and atrophy in adulthood. Detailed clinical descriptions are provided in the Supplementary material. Elevated blood or CSF lactate was noted in all the live-born neonatal subjects but not in Subject S5 (Table 1). Borderline deficiencies of OXPHOS enzymes were observed in tissues or cell lines from some patients, but these features were variable and did not lead to definitive diagnosis of mitochondrial disease (Table 1 and Supplementary Table 1; see also de Koning et al., 1999).

Table 1

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Clinical and laboratory findings in individuals with deletions in the ATAD3 gene cluster

Subject ID	Sex Ethnicity Consanguinity	ATAD3 deletion	Age at onset	Age at death	Symptoms	Brain imaging	Mitochondrial investigations
S1a	Female Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	38 weeks gestation	Day 5	Polyhydramnios, reduced foetal and no postnatal spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar and brainstem hypoplasia with simplified anterior gyral pattern anteriorly, diffuse white matter signal abnormality, marked ex vacuo ventricular dilatation consistent with global atrophy	Plasma lactate elevated up to 6.2 mM, borderline low CI, CIII, CIV in skeletal muscle but normal in skin fibroblasts. Decreased steady state levels of a critical CI and CIV subunit in fibroblasts and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors.
S1b	Male Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	33 weeks gestation	Day 1	Reduced foetal movements, foetus died intrapartum during a lengthy labour	Not performed	Borderline-low CI, CIII, CIV in skeletal muscle and borderline- low CI, CII, CIII in liver.
S2	Female Dutch Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	33 weeks gestation	Day 5	Polyhydramnios and lack of foetal movements. Caesarean section at 33 weeks due to foetal distress. No spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar hypoplasia, abnormalities of cortical gyration and periventricular white matter abnormalities	Plasma lactate elevated (2.7 to 4.4 mM), elevated urine 3-methylglutaconate and 3-methylglutatarate. Decreased CI, CIII, CIV in skin fibroblasts but normal in skeletal muscle and liver.
S3	Male Indian Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	34 weeks gestation	Day 2	Polyhydramnios. Caesarean section at 33 weeks due to foetal distress. Required ventilation, dysmorphic features, severe encephalopathy	Pontocerebellar hypoplasia, supratentorial white matter and cortical abnormalities, ventricular dilatation, simplified gyral pattern	Plasma lactate levels slightly elevated at 2.6 mM.
S4	Male Japanese Non-consanguineous	ATAD3B/ATAD3A 38 054 and 38 667 bp deletions	37 weeks gestation	7 months and 10 days	Reduced foetal movements, spontaneous delivery, cyanosis, no spontaneous respiration with Apgar score of 6/6, required ventilation throughout his life. Progressive cardiac hypertrophy	Cerebral, cerebellar and brain stem atrophy, simplified gyral pattern in the frontal lobes, haemorrhage from bilateral lateral ventricles	CSF lactate elevated (3.4 mM). Low oxygen consumption rate in skin fibroblasts but activities of CI, CII, CII+III, CIII and CIV were normal.
S5	Female French Non-consanguineous	ATAD3C/ATAD3B deletion ATAD3B/ATAD3A genomic rearrangement	Childhood	Alive at 30 years	Moderate mental retardation since childhood, dystonia, psychiatric problems, cerebellar ataxia since about 25 years	Cerebellar atrophy	Normal metabolic investigations. Normal histological analysis of muscle biopsy. In fibroblasts, decreased steady state levels of a critical CI and CIV subunit, and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors (albeit less pronounced than for Subject S1a).

Subject ID	Sex Ethnicity Consanguinity	ATAD3 deletion	Age at onset	Age at death	Symptoms	Brain imaging	Mitochondrial investigations
S1a	Female Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	38 weeks gestation	Day 5	Polyhydramnios, reduced foetal and no postnatal spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar and brainstem hypoplasia with simplified anterior gyral pattern anteriorly, diffuse white matter signal abnormality, marked ex vacuo ventricular dilatation consistent with global atrophy	Plasma lactate elevated up to 6.2 mM, borderline low CI, CIII, CIV in skeletal muscle but normal in skin fibroblasts. Decreased steady state levels of a critical CI and CIV subunit in fibroblasts and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors.
S1b	Male Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	33 weeks gestation	Day 1	Reduced foetal movements, foetus died intrapartum during a lengthy labour	Not performed	Borderline-low CI, CIII, CIV in skeletal muscle and borderline- low CI, CII, CIII in liver.
S2	Female Dutch Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	33 weeks gestation	Day 5	Polyhydramnios and lack of foetal movements. Caesarean section at 33 weeks due to foetal distress. No spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar hypoplasia, abnormalities of cortical gyration and periventricular white matter abnormalities	Plasma lactate elevated (2.7 to 4.4 mM), elevated urine 3-methylglutaconate and 3-methylglutatarate. Decreased CI, CIII, CIV in skin fibroblasts but normal in skeletal muscle and liver.
S3	Male Indian Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	34 weeks gestation	Day 2	Polyhydramnios. Caesarean section at 33 weeks due to foetal distress. Required ventilation, dysmorphic features, severe encephalopathy	Pontocerebellar hypoplasia, supratentorial white matter and cortical abnormalities, ventricular dilatation, simplified gyral pattern	Plasma lactate levels slightly elevated at 2.6 mM.
S4	Male Japanese Non-consanguineous	ATAD3B/ATAD3A 38 054 and 38 667 bp deletions	37 weeks gestation	7 months and 10 days	Reduced foetal movements, spontaneous delivery, cyanosis, no spontaneous respiration with Apgar score of 6/6, required ventilation throughout his life. Progressive cardiac hypertrophy	Cerebral, cerebellar and brain stem atrophy, simplified gyral pattern in the frontal lobes, haemorrhage from bilateral lateral ventricles	CSF lactate elevated (3.4 mM). Low oxygen consumption rate in skin fibroblasts but activities of CI, CII, CII+III, CIII and CIV were normal.
S5	Female French Non-consanguineous	ATAD3C/ATAD3B deletion ATAD3B/ATAD3A genomic rearrangement	Childhood	Alive at 30 years	Moderate mental retardation since childhood, dystonia, psychiatric problems, cerebellar ataxia since about 25 years	Cerebellar atrophy	Normal metabolic investigations. Normal histological analysis of muscle biopsy. In fibroblasts, decreased steady state levels of a critical CI and CIV subunit, and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors (albeit less pronounced than for Subject S1a).

Table 1

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Clinical and laboratory findings in individuals with deletions in the ATAD3 gene cluster

Subject ID	Sex Ethnicity Consanguinity	ATAD3 deletion	Age at onset	Age at death	Symptoms	Brain imaging	Mitochondrial investigations
S1a	Female Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	38 weeks gestation	Day 5	Polyhydramnios, reduced foetal and no postnatal spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar and brainstem hypoplasia with simplified anterior gyral pattern anteriorly, diffuse white matter signal abnormality, marked ex vacuo ventricular dilatation consistent with global atrophy	Plasma lactate elevated up to 6.2 mM, borderline low CI, CIII, CIV in skeletal muscle but normal in skin fibroblasts. Decreased steady state levels of a critical CI and CIV subunit in fibroblasts and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors.
S1b	Male Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	33 weeks gestation	Day 1	Reduced foetal movements, foetus died intrapartum during a lengthy labour	Not performed	Borderline-low CI, CIII, CIV in skeletal muscle and borderline- low CI, CII, CIII in liver.
S2	Female Dutch Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	33 weeks gestation	Day 5	Polyhydramnios and lack of foetal movements. Caesarean section at 33 weeks due to foetal distress. No spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar hypoplasia, abnormalities of cortical gyration and periventricular white matter abnormalities	Plasma lactate elevated (2.7 to 4.4 mM), elevated urine 3-methylglutaconate and 3-methylglutatarate. Decreased CI, CIII, CIV in skin fibroblasts but normal in skeletal muscle and liver.
S3	Male Indian Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	34 weeks gestation	Day 2	Polyhydramnios. Caesarean section at 33 weeks due to foetal distress. Required ventilation, dysmorphic features, severe encephalopathy	Pontocerebellar hypoplasia, supratentorial white matter and cortical abnormalities, ventricular dilatation, simplified gyral pattern	Plasma lactate levels slightly elevated at 2.6 mM.
S4	Male Japanese Non-consanguineous	ATAD3B/ATAD3A 38 054 and 38 667 bp deletions	37 weeks gestation	7 months and 10 days	Reduced foetal movements, spontaneous delivery, cyanosis, no spontaneous respiration with Apgar score of 6/6, required ventilation throughout his life. Progressive cardiac hypertrophy	Cerebral, cerebellar and brain stem atrophy, simplified gyral pattern in the frontal lobes, haemorrhage from bilateral lateral ventricles	CSF lactate elevated (3.4 mM). Low oxygen consumption rate in skin fibroblasts but activities of CI, CII, CII+III, CIII and CIV were normal.
S5	Female French Non-consanguineous	ATAD3C/ATAD3B deletion ATAD3B/ATAD3A genomic rearrangement	Childhood	Alive at 30 years	Moderate mental retardation since childhood, dystonia, psychiatric problems, cerebellar ataxia since about 25 years	Cerebellar atrophy	Normal metabolic investigations. Normal histological analysis of muscle biopsy. In fibroblasts, decreased steady state levels of a critical CI and CIV subunit, and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors (albeit less pronounced than for Subject S1a).

Subject ID	Sex Ethnicity Consanguinity	ATAD3 deletion	Age at onset	Age at death	Symptoms	Brain imaging	Mitochondrial investigations
S1a	Female Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	38 weeks gestation	Day 5	Polyhydramnios, reduced foetal and no postnatal spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar and brainstem hypoplasia with simplified anterior gyral pattern anteriorly, diffuse white matter signal abnormality, marked ex vacuo ventricular dilatation consistent with global atrophy	Plasma lactate elevated up to 6.2 mM, borderline low CI, CIII, CIV in skeletal muscle but normal in skin fibroblasts. Decreased steady state levels of a critical CI and CIV subunit in fibroblasts and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors.
S1b	Male Iranian Consanguineous	ATAD3B/ATAD3A 38 054 bp deletion	33 weeks gestation	Day 1	Reduced foetal movements, foetus died intrapartum during a lengthy labour	Not performed	Borderline-low CI, CIII, CIV in skeletal muscle and borderline- low CI, CII, CIII in liver.
S2	Female Dutch Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	33 weeks gestation	Day 5	Polyhydramnios and lack of foetal movements. Caesarean section at 33 weeks due to foetal distress. No spontaneous movements, required ventilation, dysmorphic features, severe encephalopathy	Cerebellar hypoplasia, abnormalities of cortical gyration and periventricular white matter abnormalities	Plasma lactate elevated (2.7 to 4.4 mM), elevated urine 3-methylglutaconate and 3-methylglutatarate. Decreased CI, CIII, CIV in skin fibroblasts but normal in skeletal muscle and liver.
S3	Male Indian Consanguineous	ATAD3B/ATAD3A 38 667 bp deletion	34 weeks gestation	Day 2	Polyhydramnios. Caesarean section at 33 weeks due to foetal distress. Required ventilation, dysmorphic features, severe encephalopathy	Pontocerebellar hypoplasia, supratentorial white matter and cortical abnormalities, ventricular dilatation, simplified gyral pattern	Plasma lactate levels slightly elevated at 2.6 mM.
S4	Male Japanese Non-consanguineous	ATAD3B/ATAD3A 38 054 and 38 667 bp deletions	37 weeks gestation	7 months and 10 days	Reduced foetal movements, spontaneous delivery, cyanosis, no spontaneous respiration with Apgar score of 6/6, required ventilation throughout his life. Progressive cardiac hypertrophy	Cerebral, cerebellar and brain stem atrophy, simplified gyral pattern in the frontal lobes, haemorrhage from bilateral lateral ventricles	CSF lactate elevated (3.4 mM). Low oxygen consumption rate in skin fibroblasts but activities of CI, CII, CII+III, CIII and CIV were normal.
S5	Female French Non-consanguineous	ATAD3C/ATAD3B deletion ATAD3B/ATAD3A genomic rearrangement	Childhood	Alive at 30 years	Moderate mental retardation since childhood, dystonia, psychiatric problems, cerebellar ataxia since about 25 years	Cerebellar atrophy	Normal metabolic investigations. Normal histological analysis of muscle biopsy. In fibroblasts, decreased steady state levels of a critical CI and CIV subunit, and RNASeq results indicative of decreased expression of a broad range of OXPHOS factors (albeit less pronounced than for Subject S1a).

Figure 1

Pedigrees and brain MRI from five unrelated families with cerebellar disorders. (A) Pedigrees and ATAD3 genotypes for available members of Families 1–5. (B) Brain MRI of Subjects S1a, S3, S4 and S5. Top row: Sagittal images of Subjects S1a, S3 and S4 in the neonatal period and Subject S5 at 22 years of age. The neonates have severe brainstem and cerebellar hypoplasia with flat pons (short arrows) and tiny cerebellar vermis (long arrows). There is increase of the tegmento-vermian angle and ex vacuo enlargement of the posterior fossa CSF spaces. Arrowheads indicate the thin corpus callosum. Stars in Subject S3 show isointense blood products within and below the fourth ventricle. Subject S5 presents with severe hypoplasia/atrophy of the cerebellar vermis (thick arrow) with ex vacuo enlargement of the fourth ventricle; brainstem and normal corpus callosum are normal. Bottom row: Axial T₂-weighted images show simplified sulcation and gyration more marked frontally (short arrow) and diffuse white matter T₂ signal abnormality (long arrow) in Subjects S1a and S4. Similar but less severe changes are seen in Subject S3 with shallow simplified sulcation. Both subjects had a thin cortical ribbon, decreased white matter volumes with marked T₂ hyperintensity, ex vacuo ventriculomegaly (stars) and prominence of the extra-axial CSF spaces in keeping with brain atrophy. Hypointense material within the lateral ventricles of Subject S3 is haemorrhage. Subject S5 has normal ventricles and subtle ‘frosted glass’ aspect of the posterior periventricular white matter (thick arrow). del = ATAD3 deletion; WT = wild-type.

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