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Table 1 Molecular and Clinical Findings in Patients with AGK Mutations

From: Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients

FEATURES

Sex/consan.

Mutation

Status

Onset of cardio-myopathy

Onset of cataract

Plasma lactic acidosis

Exercise intolerance

Motor develop. delay

Muscle weak.

Muscular hypotonia

Tachydys-pnea

OXPHOS defect

Other clinical features

Case-1

Male/+

c.523_524delAT (p.Ile175Tyrfs*2)¥

Dead 7 m

5 m

1 m

+

Feeding difficulty

+

+

+

+

 

Nystagmus, floppy infant

Case-2A

Male/- (Fm)

c.424-1G>A (splicing defect)¥

Dead 10 d

Birth

Birth

+

-

-

-

-

+

 

-

Case-3A

Female/- (Fm)

c.424-1G>A (splicing defect)¥

Dead 4 m

Birth

Birth

+

Feeding difficulty

-

-

-

-

 

Eosinophilia

Case-4

Female/- (Fm)

c.409C>T (p.Arg137*)¥

Dead 3 m

+

 

+

    

+

I

Esotropia, IUR, feeding problems, MMA elevation in urines (14 , N>8), total and free carnitine elevation in blood, fatty infiltrations in heart biopsy

Case-5

Male/-

c.409C>T (p.Arg137*)¥

Dead 6 m

Birth

Birth

+

Feeding difficulty

+

+

+

+

I

Esotropia, nystagmus, floppy infant

Case-6

Male/- (Fm)

c.871C>T (p.Gln291*), c.1035dup (p.Ile346Tyrfs*39)

Alive 3 m

Birth

Birth

+

-

Mild retardation

Mild

Mild

+ RSV pneumonia

 

-

Case-7

Female/-

c.297+2T>C (p.Lys75Glnfs*12), c.841C>T (p.Arg281*)

Alive 10 y

Birth

Birth

-

+

+

+

+

-

I

Cervical meningocele, ragged red fibers (15%), COX-deficient fibres (1-2%)

Case-8

Male/+

c.877+3G>T (splicing defect)¥

Alive 15 y

+

Birth

-

+

+

-

-

-

  

PC-1 [4]

Male/-

c.3G>C (p.Met1?), c.517C>T (p.Gln173*)

Alive 36 y

+

3 m

+

+

+

-

-

-

 

Floppy infant

PC-2 [4]

Male/- (Fm)

c.3G>C (p.Met1?), c.672C>A (p.Tyr224*)

Alive 35 y

+

3 m

On exercise

+

+

-

-

-

-

-

PC-3B[4]

Male/- (Fm)

c.1131+5G>A (splicing defect)¥

Dead 12 y

+

18 m

-

+

-

+

+

-

I, II+III, IV, V, PDHc

-

PC-4B[4]

Female/- (Fm)

c.1131+5G>A (splicing defect)¥

Alive 10 y

+

5 m

+

+

-

-

-

-

I, II+III, IV, V, PDHc

-

PC-5 [4]

Female/+

c.1131+5G>A (splicing defect)¥

Alive 41 y

+

Birth

+

 

+

-

-

-

V

Stroke

PC-6 [4]

Female/-

c.221+1G>A (splicing defect), c.1213C>T (p.Gln405*)

Alive 12 y

+

Birth

+

-

-

+

-

-

I, II, III, IV, very high CS

-

PC-7 [4]

Male/- (Fm)

c.412C>T (p.Arg138*), c.1137_1143del (p.Gly380Leufs*16)

Dead 11 m

+

Birth

On exercise

-

Moderate retardation

-

+

-

-

Fatty infiltrations in muscle biopsy

PC-8 [4]

Female/-

c.672C>A (p.Tyr224*), c.870del (p.Gln291Argfs*8)

Dead 10 m

+

4 m

+

-

-

-

-

-

I, II, III, IV, V, very high CS

-

PC-9 [4]

Male/-

c.101+?_222-?del (ND)¥

Dead 8 m

+

Birth

+

-

-

-

-

-

I, II, III, IV, V, very high CS

Axial hypotonia, upper left limbs paresis, seizures, brain ventricles dilation

PC-10 [4]

Male/-

c.306C>T (p.Tyr102*), c.841C>T (p.Arg281*)

Dead 18 d

+

Birth

+

-

-

-

-

+

I, II+III, IV, V

-

PC-11 [16]

Female/-

c.297+2T>C (p.Lys75Glnfs*12), c.1170T>A (p.Tyr390*)

Dead 18 y

+

<1 year

+

  

+

  

I, III, IV

Fatigue, failure to thrive, recurrent headaches, osteopenia and premature ovarian failure, severe mtDNA depletion in skeletal muscle

PC-12 [16]

Female/+

c.1131+1G>T (p.Ser350Glufs*19)¥

Dead 4 d

 

Birth

+

   

+

+

I, III, IV

Pulmonary hypertension, marked respiratory

distress, thrombocytopenia, severe mtDNA depletion in skeletal muscle

PC-13 [6]

Female/+

c.979A>T (p.Lys327*)¥

Dead 5 m

Birth

Birth

+

      

Upper respiratory tract infection

PC-14 [6]

Female/+

c.979A>T (p.Lys327*)¥

Dead 12 d

Birth

Birth

+

     

I, I+III, II+III, III, IV, high CS

 

PC-15 [6]

Male/+

c.979A>T (p.Lys327*)¥

Dead 2 d

Birth

Birth

        

PC-16 [6]

Male/+

c.979A>T (p.Lys327*)¥

Dead 18 d

Birth

Birth

        

PC-17 [6]

Male/+

c.3G>A (p.Met1?)¥

Dead 6 m

Birth

Birth

+

 

+

+

   

Cerebellar non-hemorrhagic stroke, ventricular , growth delayfibrillation

PC-18 [6]

Male/+

c.3G>A (p.Met1?)¥

Alive 2 y

2 m

Birth

-

 

-

-

-

  

Cerebellar non-hemorrhagic stroke, ventricular, modest growth delayfibrillation

PC-19 [18]

Female/+

c.424-3C>G (p.Ala142Thrfs*4)¥

Alive 17 y

-

Birth

-

-

-

-

-

-

 

Urine organic acid profile: moderately elevated lactate, 3-hydroxyisovaleric, 3-methylglutaric and 3-methylglutaconic acids

PC-20 [18]

Male/+

c.424-3C>G (p.Ala142Thrfs*4)¥

Alive 11 y

-

Birth

-

-

-

-

-

-

 

Urine organic acid profile showed moderately elevated lactate, 3-hydroxyisovaleric, 3-methylglutaric and 3-methylglutaconic acids

PC-21 [18]

Male/+

c.424-3C>G (p.Ala142Thrfs*4)¥

Alive 7 y

-

Birth

-

-

-

-

-

-

 

Urine organic acid profile showed moderately elevated lactate, 3-hydroxyisovaleric, 3-methylglutaric and 3-methylglutaconic acids

SUMMARY

17 M: 12 F/13 consan.

20 homozygous; 19 different mutations

17 †; 16 † <1 y

25/29; 10 at birth

28/29 up to 18 m; 21 at birth

20/27

6/16; + 3 feeding difficulties

10/22

8/23

7/22

7/22

3 only I; 1 only V; 9 combined

 
  1. +: presence of condition, −: absence of condition, unknown when empty.
  2. I: complex I, II+III: succinate cytochrome c oxidoreductase, IV: cytochrome c oxidase, V: oligomycin-sensitive ATPase, CS: citrate synthase, OXPHOS: oxidative phosphorylation, PDHc: pyruvate dehydrogenase complex;
  3. Fm: familial, ND: not determined;
  4. d: day, m: month, y: year;
  5. ACases 2 and 3 are siblings;
  6. BPC-3 and PC-4 are siblings;
  7. ¥Homozygous mutation.