Table 3. [Genetic Disorders to Consider in...]. - GeneReviews®

PhK Deficiency Type	Disorder	MOI	Overlapping Features	Distinguishing Features	Gene(s)	Enzyme
Liver PhK deficiency	Glycogen storage disease type VI	AR	Clinical features can be indistinguishable.	In liver PhK deficiency: low liver glycogen phosphorylase activity on in vitro assay ¹	PYGL	Glycogen phosphorylase, liver form
Glycogen storage disease type I (GSD I)	AR	Hepatomegaly Hypoglycemia	In GSD I: Severe fasting lactic acidosis Hyperuricemia Significant hyperlipidemia Neutropenia In PhK deficiency: ketosis usually present	G6PC1, SLC37A4	Glucose-6-phosphatase Glucose-6-phosphate exchanger SLC37A4
Glycogen storage disease type III (GSD III)	AR	Hepatomegaly Hyperlipidemia Hypoglycemia & ketosis	In GSD III: hypoglycemia more severe & muscle involvement w/↑ CK concentrations	AGL	Glycogen-debranching enzyme
Glycogen storage disease type IV (GSD IV)	AR	Hepatomegaly Liver cirrhosis Liver dysfunction	In GSD IV: Hypoglycemia & ketosis not typically seen No hypoglycemia in initial stages Accumulation of an abnormal glycogen (amylopectin) in liver & other tissues	GBE1	1,4-alpha-glucan-branching enzyme
Fructose-1,6-bisphosphatase deficiency (Note: Other disorders of gluconeogenesis can also be considered. ²)	AR	↑ uric acid, AST, ALT Fasting hypoglycemia & hyperlacticacidemia Hepatomegaly	In disorders of gluconeogenesis: hypoglycemia after more prolonged (e.g., overnight) fasting or during intercurrent illness w/↓ carbohydrate intake	FBP1	Fructose-1,6-bisphosphatase 1
Alpha-1 antitrypsin deficiency ³	AR	↑ AST, ALT Hepatomegaly	In alpha-1-antitrypsin deficiency: lack of fasting hypoglycemia & hyperlacticacidemia	SERPINA1	Alpha-1 antitrypsin
Deoxyguanosine kinase deficiency (mitochondrial DNA depletion syndrome 3)	AR	Hepatomegaly Hypoglycemia	In deoxyguanosine kinase deficiency: Neurologic abnormalities Lactic acidosis	DGUOK	Mitochondrial respiratory chain complexes (I, III, IV, V)
Mitochondrial complex V (ATP synthase) deficiency (OMIM 604273)	AR	Hepatomegaly	In mitochondrial complex V deficiency: Ataxia Lactic acidosis	ATPAF2	ATP synthase
Glycerol kinase deficiency (OMIM 307030)	XL	Hypoglycemia	In glycerol kinase deficiency: Ketoacidosis Extremely elevated glycerol	GK	Glycerol kinase
Niemann-Pick disease type B ⁴ (See Acid Sphingomyelinase Deficiency.)	AR	Growth restriction Hepatomegaly Hyperlipidemia	In Niemann-Pick disease type B: Lack of fasting hypoglycemia Significant splenomegaly Storage cells characteristic of disease Other features incl bone & pulmonary involvement	SMPD1	Sphingomyelin phosphodiesterase
Gaucher disease ⁴	AR	Hepatomegaly	In Gaucher disease: Lack of fasting hypoglycemia Significant splenomegaly Storage cells characteristic of the disease Other features incl bone involvement Early-onset thrombocytopenia	GBA	Glucosylceramidase
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency ⁵ (See Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency.)	AR	Hepatomegaly Hypoglycemia	In LCHAD deficiency: Cardiomyopathy Peripheral neuropathy Retinopathy	HADHA	Trifunctional enzyme subunit alpha, mitochondrial
Fanconi-Bickel syndrome (OMIM 227810)	AR	Hepatomegaly Hypoglycemia	In Fanconi-Bickel syndrome: Splenomegaly Rickets Renal tubular dysfunction Hyperphosphatemia	SLC2A2	Solute carrier family 2, facilitated glucose transporter member 2
Liver PhK deficiency & Muscle PhK deficiency	VLCAD deficiency	AR	Exercise intolerance Hepatomegaly Hypoglycemia Hypotonia Muscle cramps Muscle pain	In early-onset form of VLCAD deficiency: Hypoketosis Cardiomyopathy Pericardial effusion Disorders distinguished by enzymatic & molecular genetic testing	ACADVL	Very long-chain specific acyl-CoA dehydrogenase, mitochondrial
Muscle PhK deficiency	Glycogen storage disease type V (GSD V) ⁶	AR	Cramps Exercise intolerance Fatigue Muscle weakness Myalgia Myoglobinuria Poor endurance	In GSD V: "second-wind" phenomenon	PYGM	Glycogen phosphorylase, muscle form
Glycogen storage disease type VII (GSDVII) ⁷ (OMIM 232800)	AR	Exercise intolerance Fatigue Muscle cramps	In GSD VII: Compensated hemolysis Hyperuricemia	PFKM	ATP-dependent 6-phosphofructokinase, muscle type
Mitochondrial myopathy	See footnote 8.	Hypoglycemia Muscle weakness Exercise intolerance	In mitochondrial myopathy: Ragged red fibers Multisystem involvement incl: abnormal eye movements, ptosis, optic neuropathy; epilepsy; sensorineural hearing loss; lactic acidemia	See footnote 8.	See footnote 8.
Myoadenylate deaminase deficiency (OMIM 615511)	AR	Exercise-induced myalgia, rhabdomyolysis, &/or ↑ serum CK	Disorders distinguished by enzymatic & molecular genetic testing	AMPD1	AMP deaminase 1
Carnitine palmitoyltransferase II deficiency	AR	↑ hepatic transaminases Hepatomegaly Hypoglycemia Myalgia Myoglobinuria	In CPT II deficiency: Hypoketosis Cardiomyopathy Arrhythmia	CPT2	Carnitine O-palmitoyltransferase 2, mitochondrial
Phosphoglycerate kinase 1 deficiency (PGK1) (OMIM 300653)	XL	Cramping, particularly w/exercise Exercise-induced myalgia Pain Progressive weakness Rhabdomyolysis &/or ↑ serum CK	In PGK1 deficiency: Hemolytic anemia Intellectual disability	PGK1	Phosphoglycerate kinase 1
Phosphoglycerate mutase deficiency (GSDX) (OMIM 261670)	AR	↑ rhabdomyolysis &/or ↑ serum CK Exercise-induced myalgia Myoglobinuria	Disorders distinguished by enzymatic & molecular genetic testing	PGAM2	Phosphoglycerate mutase 2
Lactate dehydrogenase deficiency (GSDXI) (OMIM 612933)	AR	Exercise-induced myalgia Exercise intolerance Fatigue Muscle cramps Rhabdomyolysis	Disorders distinguished by enzymatic & molecular genetic testing	LDHA	L-lactate dehydrogenase A chain

PhK Deficiency
Type

Disorder

MOI

Overlapping Features

Distinguishing Features

Gene(s)

Enzyme

Liver PhK
deficiency

Glycogen storage disease type VI

Clinical features can be indistinguishable.

In liver PhK deficiency: low liver glycogen phosphorylase activity on in vitro assay ¹

PYGL

Glycogen phosphorylase, liver form

Glycogen storage disease type I
(GSD I)

Hepatomegaly
Hypoglycemia

In GSD I:

Severe fasting lactic acidosis
Hyperuricemia
Significant hyperlipidemia
Neutropenia

In PhK deficiency: ketosis usually present

G6PC1,
SLC37A4

Glucose-6-phosphatase
Glucose-6-phosphate exchanger SLC37A4

Glycogen storage disease type III
(GSD III)

Hepatomegaly
Hyperlipidemia
Hypoglycemia & ketosis

In GSD III: hypoglycemia more severe & muscle involvement w/↑ CK concentrations

AGL

Glycogen-debranching enzyme

Glycogen storage disease type IV (GSD IV)

Hepatomegaly
Liver cirrhosis
Liver dysfunction

In GSD IV:

Hypoglycemia & ketosis not typically seen
No hypoglycemia in initial stages
Accumulation of an abnormal glycogen (amylopectin) in liver & other tissues

GBE1

1,4-alpha-glucan-branching enzyme

Fructose-1,6-bisphosphatase deficiency (Note: Other disorders of gluconeogenesis can also be considered. ²)

↑ uric acid, AST, ALT
Fasting hypoglycemia & hyperlacticacidemia
Hepatomegaly

In disorders of gluconeogenesis: hypoglycemia after more prolonged (e.g., overnight) fasting or during intercurrent illness w/↓ carbohydrate intake

FBP1

Fructose-1,6-bisphosphatase 1

Alpha-1 antitrypsin deficiency ³

↑ AST, ALT
Hepatomegaly

In alpha-1-antitrypsin deficiency: lack of fasting hypoglycemia & hyperlacticacidemia

SERPINA1

Alpha-1 antitrypsin

Deoxyguanosine kinase deficiency (mitochondrial DNA depletion syndrome 3)

Hepatomegaly
Hypoglycemia

In deoxyguanosine kinase deficiency:

Neurologic abnormalities
Lactic acidosis

DGUOK

Mitochondrial respiratory chain complexes (I, III, IV, V)

Mitochondrial complex V (ATP synthase) deficiency (OMIM 604273)

Hepatomegaly

In mitochondrial complex V deficiency:

Ataxia
Lactic acidosis

ATPAF2

ATP synthase

Glycerol kinase deficiency (OMIM 307030)

Hypoglycemia

In glycerol kinase deficiency:

Ketoacidosis
Extremely elevated glycerol

Glycerol kinase

Niemann-Pick disease type B ⁴ (See Acid Sphingomyelinase Deficiency.)

Growth restriction
Hepatomegaly
Hyperlipidemia

In Niemann-Pick disease type B:

Lack of fasting hypoglycemia
Significant splenomegaly
Storage cells characteristic of disease
Other features incl bone & pulmonary involvement

SMPD1

Sphingomyelin phosphodiesterase

Gaucher disease ⁴

Hepatomegaly

In Gaucher disease:

Lack of fasting hypoglycemia
Significant splenomegaly
Storage cells characteristic of the disease
Other features incl bone involvement
Early-onset thrombocytopenia

GBA

Glucosylceramidase

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency ⁵ (See Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency.)

Hepatomegaly
Hypoglycemia

In LCHAD deficiency:

Cardiomyopathy
Peripheral neuropathy
Retinopathy

HADHA

Trifunctional enzyme subunit alpha, mitochondrial

Fanconi-Bickel syndrome (OMIM 227810)

Hepatomegaly
Hypoglycemia

In Fanconi-Bickel syndrome:

Splenomegaly
Rickets
Renal tubular dysfunction
Hyperphosphatemia

SLC2A2

Solute carrier family 2, facilitated glucose transporter member 2

Liver PhK
deficiency &
Muscle PhK
deficiency

VLCAD deficiency

Exercise intolerance
Hepatomegaly
Hypoglycemia
Hypotonia
Muscle cramps
Muscle pain

In early-onset form of VLCAD deficiency:

Hypoketosis
Cardiomyopathy
Pericardial effusion

Disorders distinguished by enzymatic &
molecular genetic testing

ACADVL

Very long-chain specific acyl-CoA dehydrogenase, mitochondrial

Muscle PhK
deficiency

Glycogen storage disease type V
(GSD V) ⁶

Cramps
Exercise intolerance
Fatigue
Muscle weakness
Myalgia
Myoglobinuria
Poor endurance

In GSD V: "second-wind" phenomenon

PYGM

Glycogen phosphorylase, muscle form

Glycogen storage disease type VII (GSDVII) ⁷
(OMIM 232800)

Exercise intolerance
Fatigue
Muscle cramps

In GSD VII:

Compensated hemolysis
Hyperuricemia

PFKM

ATP-dependent 6-phosphofructokinase, muscle type

Mitochondrial myopathy

See
footnote
8.

Hypoglycemia
Muscle weakness
Exercise intolerance

In mitochondrial myopathy:

Ragged red fibers
Multisystem involvement incl: abnormal eye movements, ptosis, optic neuropathy; epilepsy; sensorineural hearing loss; lactic acidemia

See footnote 8.

Myoadenylate deaminase deficiency (OMIM 615511)

Exercise-induced myalgia, rhabdomyolysis, &/or ↑ serum CK

Disorders distinguished by enzymatic &
molecular genetic testing

AMPD1

AMP deaminase 1

Carnitine palmitoyltransferase II deficiency

↑ hepatic transaminases
Hepatomegaly
Hypoglycemia
Myalgia
Myoglobinuria

In CPT II deficiency:

Hypoketosis
Cardiomyopathy
Arrhythmia

CPT2

Carnitine O-palmitoyltransferase 2, mitochondrial

Phosphoglycerate kinase 1 deficiency (PGK1) (OMIM 300653)

Cramping, particularly w/exercise
Exercise-induced myalgia
Pain
Progressive weakness
Rhabdomyolysis &/or ↑ serum CK

In PGK1 deficiency:

Hemolytic anemia
Intellectual disability

PGK1

Phosphoglycerate kinase 1

Phosphoglycerate mutase deficiency (GSDX) (OMIM 261670)

↑ rhabdomyolysis &/or ↑ serum CK
Exercise-induced myalgia
Myoglobinuria

Disorders distinguished by enzymatic &
molecular genetic testing

PGAM2

Phosphoglycerate mutase 2

Lactate dehydrogenase deficiency (GSDXI) (OMIM 612933)

Exercise-induced myalgia
Exercise intolerance
Fatigue
Muscle cramps
Rhabdomyolysis

Disorders distinguished by enzymatic &
molecular genetic testing

LDHA

L-lactate dehydrogenase A chain

From: Phosphorylase Kinase Deficiency

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