Table 2 Genotype–Phenotype Correlations in PMM2-CDG

C9Y

D148 N

Mild

Ataxia, Failure to Thrive (FTT), Gastroesophageal (GE) reflux, Hydronephrosis, Hypotonia, Impaired development, Lipodystrophy, Microcephaly, Mild vermal cerebellar atrophy

1

[79]

T18S

V67G

Mild

Ataxia, Impaired development, Intention tremors, Mild dysmorphic features, Normal neuroimaging

1

[21]

R21G

R21G

Severe

Severe lymphatic oedema

1

[74]

L32R

R123Q

Mild

Extra-neurological features, Mild intellectual disability, Moderate cerebellar hypoplasia, Visual defects

1

[7]

R141H

Mild

Ataxia, Cerebellar hypoplasia, Dysmorphic features, Early esotropia, Hypotonia, Impaired development, Microcephaly, Mild intellectual disability, Osteoporosis or osteopenia, Small size according to weight, Titubation, Visual defects

10

[7, 22, 79]

F157S

Mild

Mild intellectual disability, Moderate to severe cerebellar hypoplasia, Visual defects

2

[7]

T237M

Mild

Extra-neurological features, Microcephaly, Moderate intellectual disability, Visual defects

2

[7]

V44 A

D65Y

Mild

Ataxia, Cerebellar hypoplasia, Growth failure, Mental retardation

1

[73]

R123Q

Severe

Convulsions, Incapacity of locomotion, Intellectual disability, Multisystem involvement, Peripheral neuropathy, Pigmentary retinopathy, Recurrent infections, Spine involvement

1

[31]

R141H

Variable

Aortic thrombosis – early death (severe) or Similar to V44 A/R123Q (mild)

2

[31, 73]

F207S

Mild

Brain atrophy, Hepatopathy, Hypotonia

1

[73]

D65Y

D65Y

Moderate

N/A

1

[60]

R123Q

Severe

Early death

2

[60]

R141H

Severe

Early death

4

[23, 60]

F157S

Severe

Early death

2

[11, 64]

N101 K

324 del g

N/A

N/A

1

[46]

L104 V

D12H

Mild

FTT, Hypergonadrotropic hypogonadism, Hypertelorism, Hypotonia, Kyphoscoliosis, Mild hyperprolactinemia and hyperthyroglobulinemia, Primary ovarian insufficiency, Strabismus

1

[45]

IVS1–1G > A

Severe

Anaemia, Coagulopathy, GE reflux, Hypertrophic cardiomyopathy, Hypoalbuminemia, Hypoglycaemia, Pericardial effusion

1

[78]

A108 V

c.511 dupA

Mild

Moderate cerebellar hypoplasia

1

[7]

70 kb-deletion

Mild

Cerebellar vermis hypoplasia, Esotropia, Feeding problems, Hyperlaxity, Hypotonia, Inverted nipples, No facial dysmorphism

1

[7]

R123Q

Severe

Convulsions, FTT, Inability to walk, Multiorgan involvement, Peripheral neuropathy, Recurrent infections, Retinitis pigmentosa, Scoliosis, Severe delayed development

1

[31]

P113L

R141H

Severe

Ataxia, Blood coagulation abnormalities, Brain hypoplasia, Disturbed development, Disturbed psychomotor abilities, Hyporeflexia, Low levels of thyroid hormones, Retinitis pigmentosa, Retracted nipples, Severe hyperinsulinemic hypoglycaemia, Strabismus

5

[10, 13,  23 ]

F157S

Moderate

Cerebellar hypoplasia, Hypotonia, Mild delayed development, Strabismus

1

[31]

T237M

Severe

Convulsions, FTT, Inability to walk, Multiorgan involvement, Peripheral neuropathy, Recurrent infections, Retinitis pigmentosa, Scoliosis, Severe delayed development

2

[31]

F119L

R141H

Severe

Early dead (6 patients), Feeding difficulties, FTT, Impaired development, Inverted nipples, Liver dysfunction, Pericardial effusion, Postnatal growth failure, Progressive brain atrophy, Serious hypotonia, Subcutaneous fat pads, Unable to walk without support

51

[23, 36, 37]

I120 T

G228 C

Mild

Ataxia, Blood coagulation abnormalities, Cerebellar vermis hypoplasia, Disturbed motor development, FTT, Impaired speech, Strabismus

1

[72]

V231M

Mild

Blood coagulation abnormalities, Hemiparesis, Seizures

1

[24]

R123Q

C241S

Mild

Ataxia, Cerebellar vermis hypoplasia, Esotropia, GE reflux, Hypotonia, Impaired development and psychomotor abilities, Mild brain atrophy, Mild lipodystrophy, Retracted nipples, Tremors

2

[14, 79]

V129L

161_162 insG

Severe

Cardiological failure, Early death, Hydrops, Hydrops fetalis and oedema, during foetal development, Hypertrophic cardiomyopathy, Hypoglycaemia, Severe amegakaryocytic thrombocytopenia

2

[81]

V129M

L32R

Mild

Moderate cerebellar hypoplasia, Moderate intellectual disability, Visual defects

2

[7]

R141H

Severe

Abnormal levels of blood coagulation factors, Ataxia, Brain atrophy, Hepatic steatosis, Microcephaly, Osteopenia, Severe cerebellar hypoplasia, Stroke-like episodes are probable, Visual defects

7

[7, 8, 23]

IVS3 + 2 C > T

Severe

Early death

1

[53]

P131 A

R141H

N/A

N/A

1

[42]

I132 F

E197 A/I132 F

N/A

N/A

1

[42]

I132 T

R123Q

Mild

Areflexia, Brain hypoplasia, Disturbed psychomotor abilities, Dysmorphism, FTT, Hepatomegaly, Hypotonia, Pericardial inflammation, Strabismus, Tubulopathy

1

[23]

R141H

Mild

Areflexia, Brain hypoplasia, Facial dysmorphism, Fat pads, Feeding problems, FTT, Hepatomegaly, Hyperprolactinemia, Hypotonia, Recurrent seizures, Retarded development and psychomotor abilities, Strabismus, Tubulopathy

4

[7, 23, 30]

F207S

Mild

GE reflux, Hepatomegaly, Hypothyroidism, Hypotonia, No fat pads, Normal neuroimaging

1

[67]

E139 K

R141H

Mild

Areflexia, Cerebellar atrophy, Disabled psychomotor capacities, Feeding problems, Hypoplasia, Hypotonia, Inverted nipples, Seizures

7

[23, 65, 76]

R141H

V43M

Mild

Disabled development, Esotropia, Hypermetropia, Hypotonia, Increased serum transaminases, Mild dysmorphism

1

[9]

A108 V

Mild

Areflexia, Cerebellar hypoplasia, Diarrhoea, Hypotonia, Psychomotor, retardation, Strabismus

1

[23]

G228 C

Mild

Brain haemorrhage, Malignant brain tumour, Typical PMM2-CDG phenotype

1

[68]

F144L

R238P

Mild

Ataxia, Dysmorphic facial traits, Feeding difficulties, Hypergonadotropic hypogonadism, Impaired motor development, Low height, Mild brain atrophy, Muscular hypotonia, Unable to speak, Rapid onset after birth, Recurrent stroke-like episodes, Seizures and hemiparesis due to several head injuries, Severe delayed development, Strabismus, Tremors, Only walk with support

2

[40]

Y229S

Mild

Ability to walk unaided, Ataxia, Brain atrophy, Disabled mental development and psychomotor abilities, Hypotonia, Increased serum transaminases, Recurrent stroke-like episodes

2

[40]

D148 N

F183S

Mild

Disabled mental development, Dysmorphism, Fat pads, Feeding difficulties, Hypotonia, Spine abnormalities, Strabismus

1

[33]

I153 T

R123Q

Severe

Convulsions, FTT, Inability to walk, Multiorgan involvement, Peripheral neuropathy, Recurrent infections, Retinitis pigmentosa, Scoliosis, Severe delayed development

1

[31]

R141H

Severe

Brain hypoplasia, Diarrhoea, Disturbed psychomotor abilities, Hypotonia, Pericarditis, Renal cysts, Seizures, Strabismus

1

[23]

F157S

V231M

Severe

Early death

1

[60]

C241S

Mild

Cerebellar hypoplasia, Hypotonia, Mild delayed development, Strabismus

2

[31, 60]

R162 W

R123X

Moderate

N/A

1

[60]

R141H

Moderate

Cerebellar hypoplasia, Hypotonia, Mild delayed development, Strabismus

1

[31]

F183S

R141H

Mild

Mild liver dysfunction, Mild peripheral neuropathy, Neurological involvement

7

[25]

F183S

Mild

Mild liver dysfunction, Mild peripheral neuropathy, Neurological involvement

1

[25]

G186R

G186R

Mild

Most of common traits of PMM2-CDG were not apparent

2

[52]

D188G

L35X

Severe

Ascites, Early death, Fat pads, FTT, Hepatic involvement, Hypoalbuminemia, Inverted nipples, Pericardial effusion, Renal involvement, Strabismus, Thrombocytopenia

1

[70]

R141H

Severe

Early death

4

[55]

F207S

Y67 C

Severe

Cerebellar hypoplasia, Dysmorphism, Early death, Hepatopathy in the neonatal period, Severe encephalopathy

1

[11]

N216I

Mild

Cerebellar hypoplasia, Convulsions, Disabled psychomotor development, Obesity, Retracted nipples

1

[11]

G208 A

R141H

Severe

Anaemia, Coagulation abnormalities, Ventricular septum defect, Pericardial effusion, Hepatic and renal involvement, Seizures, Multiorgan failure—early death; Severe pericardial effusion, left ventricle failure—early death

2

[2, 32, 33]

N216I

R141H

Severe

Cerebellar hypoplasia, Extra-neurological features, Microcephaly, Moderate to severe intellectual disability, Stroke-like episodes, Visual defects

3

[7]

N216I

Mild

Brain hypoplasia and dilatation of the 4 th ventricle, Hypotonia, Macrosomia, Mild psychomotor disability, Recurrent respiratory tract infections, Strabismus

1

[49]

D223E

N/A

N/A

Nearly total loss of PMM activity in fibroblasts

1

[38]

D223 N

G15E

Severe

Brain hypoplasia, Inability to walk without support, Intellectual disability, Severe microcephaly, Stroke-like episodes, Visual defects

1

[7]

R141H

Severe

Microcephaly, Severely impaired intellectual development

1

[7]

T226S

R141H

Mild/moderate

Cerebellar hypoplasia, Hypotonia, Psychomotor disability, Strabismus

2

[23, 31]

G228 C

I120 T

Mild

Ataxia, Cerebellar hypoplasia with vermis hypoplasia, Disturbed fine motor skills, Dysarthric speech, Hypotonia, Strabismus

1

[72]

V231M

R141H

Severe

Incapability of walking without support, Microcephaly, Multisystem involvement (neurological manifestations, vomiting, and renal involvement), Severe cerebellar hypoplasia, Severe intellectual disability, Two early deaths derived from cardiological involvement, Two early deaths due to multiorgan involvement

8

[6, 7, 23]

T237R

Severe

Cardiological and respiratory failure led to early death

1

[5]

R239 W

Mild/moderate

Appropriate cognitive development

3

[72]

T237R

T237M/(T237R + A233 T)

Severe

Convulsions, FTT, Inability to walk, Multiorgan involvement, Peripheral neuropathy, Recurrent infections, Retinitis pigmentosa, Scoliosis, Severe delayed development

1

[31]

C241S

Mild

Mild intellectual impairment, Moderate cerebellar hypoplasia

1

[7]

T237M

R141H

Mild

Ataxia, FTT, Impaired development, Mild dysmorphism, Mild retinal dysfunction, Severe muscle hypotonia, Tremors

1

[33]

^a

Mild

Abnormal fat distribution, Amblyopia, Dysmorphic traits, FTT, GE reflux, Impaired development, Inability to walk without support, Mild brain hypoplasia, Muscle hypotonia, Retracted nipples, Strabismus

1

[69]

R238P

R194X

Moderate

FTT, Recurrent non-epileptic seizures, Impaired development, Hepatomegaly, Increased serum transaminases, decreased serum ceruloplasmin

1

[17]

R239 W

V231M

Mild

Appropriate to mild delayed cognitive development, Cerebellar hypoplasia, Hypotonia, Strabismus

5

[31, 72]

C241S

R141H

Mild

Mild impaired motor development, No coagulation abnormalities, No hepatic dysfunction

7

[7, 23, 60, 72]