Table 1.

Simplified phenotypic features and genotype of 22 subjects with PSMF1-related disorder belonging to 15 families

Pedigree		Pedigree A	Pedigree B		Pedigree C	Pedigree D	Pedigree E	Pedigree F	Pedigree G	Pedigree H
Individual		A-II-2	B-II-3	B-II-4	C-II-2	D-II-4	E-II-3	F-II-1	G-II-3	H-II-1	H-II-3
Sex/Current age		M/25–30 yrs	F/35–40 yrs	M/35–40 yrs	M/Deceased (40–45 yrs)	F/Deceased (65–70 yrs)	M/30–35 yrs	M/30–35 yrs	M/15–20 yrs	F/Deceased (15–20 yrs)	M/15–20 yrs
Parental consanguinity		No	Yes	Yes	Yes	No	Yes	Yes	No	No	No
Family history		Unremarkable	One sibling affected	One sibling affected	PD; deaths in childhood	Unremarkable	Unremarkable	Unremarkable	Unremarkable	One sibling affected	One sibling affected
Core phenotype		Parkinsonism	Parkinsonism	Parkinsonism	Parkinsonism	Parkinsonism	Parkinsonism	Parkinsonism	Parkinsonism	Parkinsonian-pyramidal syndrome	Spastic-ataxia syndrome
Age at onset		20–25 yrs	15–20 yrs	15–20 yrs	25–30 yrs	45–50 yrs	15–20 yrs	0–5 yrs	0–5 yrs	0–5 yrs	0–5 yrs
Symptom at onset		Bradykinesia, dysphagia, anxiety	Right hand tremor	Right hand tremor	Micrographia	Left upper limb tremor	Hand tremor, left foot dragging, anxiety	Dystonic head tremor	Clumsiness, frequent falls without fall reflex	Limb spasticity	Limb spasticity
Neurological manifestations
	Motor features	Parkinsonism. Eye movement abnormalities. Dysarthria. Gait festination. Balance difficulty. Pyramidal signs. Mild cerebellar signs.	Parkinsonism. Dysarthria. Freezing of gait. Balance difficulty.	Parkinsonism. Blepharospasm. Dysarthria. Postural and kinetic tremor. Freezing of gait to tiptoe walking. Pyramidal signs.	Parkinsonism. Blepharospasm. Pyramidal signs. Freezing of gait Falls. Tiptoe walking.	Parkinsonism. Restless leg syndrome. Freezing of gait.	Parkinsonism. Postural tremor. Pyramidal signs.	Tremulous segmental dystonia. Parkinsonism.	Parkinsonism. Action tremor. Blepharospasm. Hyperreflexia. Myoclonus. Frequent episodes of freezing.	Parkinsonism. Pyramidal signs. Ataxia.	MDD. Pyramidal signs. Ataxia.
	Response to treatment	Mild-to-moderate response to LD. Early-onset LD-induced dyskinesia.	Mild-to-moderate response to LD. Early-onset LD-induced dyskinesia.	No response to LD. Mild response to DA. Early-onset dyskinesia.	Initial good response to LD. Severe motor fluctuations and LD-induced dyskinesia. Initial good response to DBS.	Initial good response to LD. Severe motor fluctuations and LD-induced dyskinesia. Initial good response to DBS.	Moderate response to LD. LD-induced dyskinesia.	Poor response to LD.	N/A	Good response to levodopa.	N/A
Brain MRI (age)		Mild cerebral atrophy, faint T2 hyperintensity in the posterior periventricular WM (20–25 yrs)	Normal.	Mild atrophy of the inferior cerebellar vermis.	Normal.	Normal.	Mild-to-moderate cerebral atrophy, thin CC, small AC, small midbrain, mild atrophy of superior cerebellar vermis (25–30 yrs)	Mild cerebellar cortical atrophy.	Retrocerebellar cyst.	Atrophy of cerebral hemispheres, basal ganglia, thalami, brainstem and cerebellum, with mineralization of the lentiform nuclei.	Mild T2 signal alterations in the anterior midbrain bilaterally.
Other instrumental investigations		DaTscan: abnormal. MIBG: normal. DEXA: osteopenia.	EEG: normal. EMG/NCS: normal.	EEG: normal. EMG/NCS: normal. Muscle biopsy: normal.	F-DOPA-PET: abnormal. FDG-PET: temporal hypometabolism.	-	US: no organomegaly. Ophthalmological assessment: normal. Normal CK, lactate, pyruvate, copper, caeruloplasmin and 24-hour urinary copper excretion.	EEG/Video-EEG: normal.	Low testosterone level. EEG: cerebral dysrhythmia. VEP: prolonged latency. Brain MRS: normal. Muscle MRI: atrophy of gluteal muscles, with increased muscle fat. DEXA: severe osteopenia.	DaTscan: abnormal.	Muscle biopsy and enzymology: normal.
Genotype PSMF1 (NM_006814.5)		C-HET c.724C>G p.(Arg242Gly) c.282+2T>A	HOM c.724C>G p.(Arg242Gly)	HOM c.724C>G p.(Arg242Gly)	HOM c.724C>T p.(Arg242Cys)	HOM c.725G>A p.(Arg242His)	HOM c.157C>A p.(Leu53Met)	HOM c.682C>G p.(Leu228Val)	C-HET c.724C>G p.(Arg242Gly) c.691C>T p.(Arg231*)	HOM c.282+5G>A	HOM c.282+5G>A

Pedigree		Pedigree I	Pedigree J			Pedigree K			Pedigree L	Pedigree M		Pedigree N	Pedigree O
Individual		I-II-3	J-II-1	J-II-3	J-II-4	K-II-1	K-II-3	K-II-6	L-II-1	M-II-4	M-II-5	N-II-3	O-II-2
Sex/Current age		M/20–25 yrs	F/10–15 yrs	F/5–10 yrs	F/5–10 yrs	F/Deceased (15–20 yrs)	F/Deceased (15–20 yrs)	M/Deceased (15–20 yrs)	F/0–1 yr	M/Deceased (0–1 yr)	F/Deceased (0–1 yr)	M/Deceased (0–1 yr)	M/Feticide (GA third trimester)
Parental consanguinity		Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No
Family history		Unremarkable	Two siblings affected	Two siblings affected	Two siblings affected	Two siblings affected	Two siblings affected	Two siblings affected	Unremarkable	One pregnancy loss; one sibling affected.	One pregnancy loss; one sibling affected.	One miscarriage	Unremarkable
Core phenotype		DD with CC agenesis	DD with CC hypoplasia	DD with CC hypoplasia	DD with CC hypoplasia	Parkinsonian-pyramidal syndrome with CC hypoplasia	Parkinsonian-pyramidal syndrome with CC hypoplasia	Parkinsonian-pyramidal syndrome with CC hypoplasia	Arthrogryposis with CC hypoplasia	Arthrogryposis	Arthrogryposis with CC agenesis	Arthrogryposis	Arthrogryposis with CC agenesis
Age at onset		Early childhood	Early childhood	Early childhood	Early childhood	10–15 yrs	10–15 yrs	Infancy	Prenatal	Prenatal	Prenatal	Prenatal	Prenatal
Symptom at onset Neurological manifestations		GDD	GDD	SLDD	GDD	Memory and attentional deficits	Memory and attentional deficits	Epilepsy	N/A	N/A*	N/A	N/A	N/A
	Motor features	Global hypokinesia. Clumsiness. Mild hypotonia.	Hypokinesia. Broad-based gait. Talipes.	Hypokinesia	Hypokinesia. Talipes.	Hypokinesia. Pyramidal tract signs.	Hypokinesia. Pyramidal tract signs.	Hypokinesia. Pyramidal tract signs.	Arthrogryposis. Limb spasticity. Increased jitteriness.	N/A*	Myoclonus. Arthrogryposis. Limb spasticity. Truncal hypotonia. GDD.	Arthrogryposis.	Arthrogryposis
	Response to treatment	N/A	Partial response to LEV. Good rresponse to CBZ and VPA	N/A	N/A	N/A	Partial response to CBZ and VPA	Unspecified response to CBZ	N/A	N/A*	Poor response to AED.	N/A	N/A
Brain MRI (age)		CC agenesis, malformation of the left cerebellar hemisphere, cerebellar vermis hypoplasia. Arachnoid cyst.	Moderate cerebral atrophy, thin CC (10–15 yrs)	N/A	N/A	Progressive mild-to-moderate cerebral atrophy, CC hypoplasia, small AC, faint periventricular T2 signal alterations, mild superior cerebellar vermis atrophy (10–15 yrs)	Moderate cerebral atrophy, CC hypoplasia, small AC, faint periventricular T2 signal alterations, mild superior cerebellar vermis atrophy (10–15 yrs)	CC hypoplasia, small ACC, faint posterior periventricular T2 signal (0–5 yrs)	CC hypoplasia. Absent myelination within the posterior portion of the internal capsule. Multiple foci of T2 hyperintensity within the lentiform nuclei (infancy).	N/A*	CC hypoplasia. Hypomyelination. Progressive cerebral atrophy. Subdural hygromas (infancy).	Cavum septum pellucidum and cavum vergae	N/A
Other investigations		Prenatal US: hydrocephalus. DEXA: osteopenia (on bisphosphonates).	EEG: multifocal epileptiform discharges	N/A	N/A	Sleep EEG (age 10–15 yrs): general disorganization of brain electrical activity without epileptiform discharges.	EEG: abnormal, with focus	EEG: initially normal, then showing epileptic activity mainly in the temporo-parietal regions.	EEG: normal. Postnatal abdominal US: normal.	N/A*	CTG: pathological. EEG: intermittent epileptic activity. Prolonged ECG: intermittent bradycardia. Postnatal echocardiography: ASD type II with left-right shunt. Spine MRI: low-lying conus medullaris.	Prenatal US: polyhydramnios, clenched fists, clubfeet. Neonatal head and spine US: reduced gyration, low-lying conus medullaris/tethered cord. EEG: pathological pattern. Postnatal echocardiography: unremarkable. Postnatal abdominal US: left hydronephrosis and hydroureter.	Prenatal US (GA 20–25 wks): normal. Prenatal US (GA 30–35 wks): polyhydramnios, suspected CC agenesis, small stomach. Prenatal US (GA 35–40 wks): fetal growth restriction, abnormal fetal movements, CC agenesis, intracerebral cyst, arthrogryposis, thickened myocardium, small stomach, left hydronephrosis and hydroureter. QF-PCR: negative. CGH: negative.
Genotype PSMF1 (NM_006814.5)		HOM c.605+1G>A	HOM c.764+5G>A	HOM c.764+5G>A	HOM c.764+5G>A	N/A	HOM c.764+5G>A	HOM c.764+5G>A	HOM c.691C>T p.(Arg231*)	N/A	HOM c.1A>T	C-HET c.101del p.(Gly34Valfs*47) c.129+2T>C	C-HET c.365+2T>C c.1A>T

Legend: AC = anterior commissure; AED = antiepileptic drugs; ASD = atrial septal defect; CBZ = carbamazepine; C-HET = compound heterozygote; CC = corpus callosum; CGH = comparative genomic hybridization; CK = creatine kinase; CTG = cardiotocography; DBS = deep brain stimulation; DD = developmental delay; DEXA = bone density scan; ECG = electrocardiogram; EEG = electroencephalogram; F = female; GA = gestational age; GDD = global developmental delay; HOM = homozygote; LEV = levetiracetam; M = male; MDD = motor developmental delay; MIBG = ¹²³I-metaiodobenzylguanidine scintigraphy; MRI = magnetic resonance imaging; MRS = magnetic resonance spectroscopy; N/A = not applicable or not available; PD = Parkinson’s disease; QF-PCR = quantitative fluorescence polymerase chain reaction; SLDD = speech and language developmental delay; US = ultrasound; VEP = visual evoked potentials; VPA = valproic acid; yr(s) = year(s); wks = weeks.

^*Clinical details not available (M-II-4 reported with a phenotype similar to his sister M-II-5).

Detailed clinical information is available upon request to the corresponding author.