Table 1 Previous reported patients in scientific literature

1

6 m

3y (Ϯ)

M

2

6w

10y

M

3

5w

5y

F

Loss of subcortical WM volume

4

72d

18 m

M

5

9 m

M

6

18 m

14y

F

7

1y

26y

F

8

1y

21y

M

9

1 m

18y

F

Y(2y)

10

1 m

15y

F

11

3 m

19 m

M

Y

Thalami, anterior commissure, anterior arms of the internal capsules, along the opticall pathways, midbrain

Y

Cerebellar dentate nuclei

12

6 m

7y

M

Y(3y)

Y(7Y)

Y(3y)

Periventricular WM, paons, thalami, internal capsules and calcarine cortex

Y

Cerebellar WM

13

6 m

18 m

F

y(6 m)

Y

Internal capsules, deep and periventricular WM

14

28y

33y (Ϯ)

F

15

Birth

12y (Ϯ)

M

Y(nascita at birth)

WM

16

Birth

2y (Ϯ)

M

Low density of WM

y(2y)

17

Birth

4y (Ϯ)

M

y(3y)

Internal capsule

18

Birth

8y (Ϯ)

M

Low density of WM

y(nascita at birth)

19

Birth

12y

M

Low density of WM

y(nascita at birth)

20

Birth

12y (Ϯ)

M

Low density of WM

y(2y)

Internal capsule

21

Birth

3y

M

22

25y

27y (Ϯ)

F

23

15y

35y

M

24

35y

32y

M

25

Birth

3y

M

Y

Cerebellar nuclei

26

Birth

12y (Ϯ)

F

Y (cerebellar white loss)

Y

Basal ganglia, frontal, parietal lobes

27

Birth

30 m (Ϯ)

F

Y

Y

Y

Semioval center, corona radiata, periventricular WM, thalamus, brainstem

Y

Dentate nucleus

1

Increased mtDNA in muscle

↑lactate and alanine

Y

2

Deep WM

3

4

5

I, IV

↑lactate

6

IV, I + IV

7

Frontal WM, corpus callosum

Y

8

Periventricular WM, corpus callosum

Y

9

Y

10

Y

11

Y

Tracl-like calcifications along the medullary pathways

U-fibers, internal and external capsules, brainstem, cerebellum

↑lactate and lipids, ↑choline/creatine, ↑myoinositol/creatine, ↓N-acetylaspartate/creatine

I, II, I + III, II + III

normal

Moderate ketosis,↑ alanin

Biopterin

Y

12

Y

C6-T1

Deep cerebellum WM, middle cerebellar peduncles, brainstem, U-fiber, posterior arm of the internal and external capsules, thalami

↓N-acetylaspartate, ↑ lactate

↑lactate and pyruvate

Hepatomegaly, ↑ transaminase

Y(profound)

13

Y(12 m)

Dentate nuclei

Centrum semiovale, corona radiata, posterior arm of the internal and external capsules, thalami, cerebellar amd deep WM and brainstem, V cranial nerves, cervical and dorsal columns

↑lactate and pyruvate

↑ transaminase, vascular disturbance with nodular regenerative hyperplasia

Y

14

Dentate nucleus, optic radiations, corpus callosum splenium

I,IV

COX-neg fibers

↑lactate

Y

15

Posterior limbs of the internal capsules, thalami

Y

16

Y(2y)

Y

17

Precentral gyri

↑lactate

Y

18

Y

↑lactate and pyruvate

Y

19

Y

↑lactate and pyruvate

Y

20

Internal capsules

↑lactate in cerebral WM

Y

21

Y (and atrophy)

Y

22

Inner capsule

Y

23

Periventricular WM

Y

24

Y

25

Abnormal ultrasound

Y

26

Deep WM of both cerebral hemispheres, corticospinal tracts

↑lactate

↑proteins

Y

27

↓NAA/Cr ratio, ↓ Cho/Cr ratio, presence of lactate

I + III, IV

↑lactate and glycine

Cirrhotic hepatopathy, polylobulated liver aspect, presence of bleeding esophageal varices, liver calcifications

Y

1

Development delay, hypotonia, dystonia

Strabism, ophtalmoplegia

c.1760C>T p.Thr587Met

c.683C>T p.Pro228Leu

Lieber (2013) Neurology 80, 1762

2

Y

Y

Nystagmus, delayed PEV

c.1396C>T p.Arg466Trp

c.1657G>A p.Glu553Lys

McMillan (2015) J Child Neurol 30, 1037

3

c.1396C>T p.Arg466Trp

c.1657G>A p.Glu553Lys

McMillan (2015) J Child Neurol 30, 1037

4

Hypertonicity, extreme irritability, psychomotor delay

Y

Y (West sindrome)

Nystagmus, abnomal ocular movements

Failure to thrive

c.169G>C p.Ala57Pro

chr16: 75,672,800–75,680,400 loss of starting codon

Joshi C. (2016) Biomed Res Int. 2016:6,421,039

5

Development delay

Y

Nystagmus

Hypertrophic cardiomyopathy

c.1427T>A p.Val476Asp

c.1037T>C p.Ile346Thr

Kohda (2016) PLoS Genet 12, e1005679

6

Mild psychomotor delay, intellectual disability, mild myopathy

Hypertrophic cardiomyopathy

c.1133T>A p.Leu378Hys

c.1253C>G p.Pro418Arg

Verrigni (2017) Clin Genet 91, 918

7

Progressiv ecognitive impairment

c.1514G>A p.Arg505Hys

c.1597C>T p.Pro533Ser

Zhou (2017) Hum Mutat 38, 1740

8

Progressiv ecognitive impairment

c.1514G>A p.Arg505Hys

c.1597C>T p.Pro533Ser

Zhou (2017) Hum Mutat 38, 1740

9

Development delay, hypotonia

Y

Y

c.1577C>T p.Ala526Val

c.1466T>G p.Phe489Cys

Murray (2017) J Pediatr Genet 6, 77

10

Development delay

Y

Y

c.1577C>T p.Ala526Val

c.1466T>G p.Phe489Cys

Murray (2017) J Pediatr Genet 6, 77

11

Severe spastic tetraplegia, progressive hypertonus, absense of voluntary movementes

Y

Hypertonic seizures

VEP and ERG mild conduction delay

c.1514G>A p.Arg505His

c.1514G>A p.Arg505His

Ardissone A (2018) Orphanet J Rare Dis 13(1):45

12

Absence of spontaneus movements and postural control, spastic tetraparesis with extrapyramidal signs, absence of language

Microcytic hypocromic anemia

Nystagmus, bilateral optic atrophy

Marked

c.1124A>G p.Tyr375Cys

c.381C>G p.Phe127Leu

Ardissone A (2018) Orphanet J Rare Dis 13(1):45

13

Spastic tetraplegia, absent postural control, poor spontaneus movements

Y

Microcytic hypocromic anemia

Delayed VEP, mild retinal depigmentation

c.815T>G p.Phe272Cys

c.1043G>A p.Arg348His

Ardissone (2018) Orphanet J Rare Dis 13(1):45

14

Cerebellar ataxia

Concentric decrease of peripheral isopter

c.683C>T p.Pro228Leu

c.871T>G p.Phe291Val

Scheidecker (2019) Hum Mutat 40, 1826

15

Hypotonia, difficulty feeding, delayed development

Y

Nystagmus

c.1786C>T p.Leu596Phe

c.1786C>T p.Leu596Phe

Itoh (2019) Brain 142(3):560–573

16

Hypotonia, severe development delay

Anemia, thrombocytopenia,

Y

Nystagmus

Distal renal tubular acidosis

c.1786C>T p.Leu596Phe

c.879 + 1G>A p.Glu252_Glu293del

Itoh (2019) Brain 142(3):560–573

17

Hypotonia, development delay

Y

Nystagmus

Distal renal tubular acidosis

c.1786C>T p.Leu596Phe

c.879 + 1G>A p.Glu252_Glu293del

Itoh (2019) Brain 142(3):560–573

18

Tetraplegia, development delay, hypotonia

Pancytopaenia

Y

Nystagmus

c.1786C>T p.Leu596Phe

c.1786C>T p.Leu596Phe

Itoh (2019) Brain 142(3):560–573

19

Hypertonia, tetraplegia, dystonia, hypotonia

Anemia

Y

c.1786C>T p.Leu596Phe

c.1786C>T p.Leu596Phe

Itoh (2019) Brain 142(3):560–573

20

Hypotonia, severe development delay

Y

Nystagmus

c.1786C>T p.Leu596Phe

c.1786C>T p.Leu596Phe

Itoh (2019) Brain 142(3):560–573

21

Hypotonia, chorea, spasticity

Anemia, hypogammaglobulinemia

Y

Nystagmus

c.1786C>T p.Leu596Phe

c.566G>A p.Gly189Asp

Itoh (2019) Brain 142(3):560–573

22

Hypotonia, intellectual disability, slurred speech, ataxia, abnormal movements

c.1514G>A p.Arg505His

c.1597C>T p. Pro533Ser

Sun (2019) Neurol Genet.5(2):e565

23

c.1514G>A p.Arg505His

c.1597C>T p. Pro533Ser

Sun (2019) Neurol Genet.5(2):e565

24

Progressive neurocognitive decline, hypertonia, abnormal movements, ataxia

Y

Left eye blindness

Primary hypothyroidism

c.881T>C p.Ile294Thr

c.1760C>T p.Thr587Met

Sun (2019) Neurol Genet.5(2):e565

25

Developmente delay, development regression, hypertonia, hyperreflexia, progressive joint contractures, dysphagia

Y

Y

Vision loss, nystagmus

Renal tubular acidosis, mild monolateral hydronephrosis, failure to thrive

c.1281_1282insAGA p.Glu427_Leu428insAeg

c.1786C>T p.Leu596Phe

Sun (2019) Neurol Genet.5(2):e565

26

Developmente delay, hypotonia, intellectual disability, development regression, ataxia

Y

c.697C>G p.Leu233Val

c.697C>G p.Leu233Val

Sun (2019) Neurol Genet.5(2):e565

27

Apostural tetraparesis, severe development delay

Y

Pancitopenia, ring sideroblasts

Y

Leopard spot retinopathy, thin pRNF, retinal thinning, strabismus, poor fixation, delayed VEP

Pulmonary valve stenosis

Failure to thrive

c.815T>G p.Phe272Cys

c.1570T>C p.Cys524Arg

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