PHOSPHOFRUCTOKINASE (PFK) DEFICIENCY

Disorder of Glycolysis//Glucose Storage Disease// type VII glycogenosis

a.k.a. TARUI DISEASE

Phosphofructokinase catalyzes the rate-limiting step in glycolysis.

PFK deficiency leads to muscle pain, exercise-induced fatigue and weakness.

resolves with rest may not progress to severe disability

PFK DEFICIENCY (TAURI DSE.) least common GSDsymptoms may be quite mild- the true incidence may be higher due to lack of recognition.

autosomal recessive pattern of inheritance Males outnumber females

PFK DEFICIENCY SUBTYPES

1) CLASSIC-most cases

2) INFANTILE ONSET

3) LATE ONSET Classic -presents in childhood with exercise intolerance and anemia.

Infantile-first year of life All patients of reported cases died by age 4 years.

 Late-onset- later adulthood progressive limb weakness without myoglobinuria or cramps

FATAL

SSx:Exertional fatigue -usual presenting symptom, more severe than in McArdle disease (glycogen storage disease type V)

exercise intolerance, fatigue, and myoglobinuria- Classic type

N/V, muscle cramps, hyperuricemia, or even frank anuria following high-intensity exercise

Blindness and psychomotor retardation -infantile-onset type Cardiac dysfunction, arrhythmia and anginal chest pain - late-onset type 

Jaundice- Hemolysis due to partial erythrocyte PFK deficiency

SSx:Classic and late-onset

Muscle weakness, most pronounced following exercise Fixed limb weakness Muscle contractures Jaundice Joint pain

Fatal infantile variant Muscle weakness Cataracts Joint contractures

Etiology/Pathophysioautosomal recessive pattern of inheritance↓ PFK ↓glycogen utilization impaired degradation or excess synthesis of glycogen Glycogen accumulation

Accumulation of hexose monophosphates activation of glycogen synthetase ↑ nucleotide formation increased uric acid production

Etiology/PathophysioPFK 3 subunits- muscle (M), liver (L), and platelet (P). M isozyme- mature muscle, brain and heart L isoform- liver and kidneys; M and L subunits- Erythrocytes

defect M isoform resulting in the absence of enzymatic activity in the muscle

Erythrocytes lack the M4 and hybrid isozymes and only express the L4 homotetramers, resulting in about 50% of normal PFK activity. Thus, hemolysis is a result of partial erythrocyte PFK deficiency.

Dx: (Blood)Serum CK- usually ↑Lactic acid does not increase following exercise.Bilirubin levels- may be ↑RET count/ RDW- ↑U/A- myoglobinuria  

Dx: (Imaging)Brain imaging scans - cortical atrophy and ventricular dilatation (inf.)

Phosphorus-31 nuclear magnetic resonance spectroscopy (31 P-NMR S) of calf muscle using a 4.7-Tesla MRI During exercise, glycolytic intermediates accumulate as phosphorylated monoesters

that are pathognomonic of Tarui disease. shows the absence of lactic acid production.

 

Dx:↓PFK enzyme activity in muscle tissue

definitive biochemical diagnosis Muscle biopsy is necessary for microscopic and biochemical assay of PFK activity.

Sequence analysis -PFKM gene Homozygous or compound heterozygous - definitive molecular diagnosis

Dx: (Other Tests) EMG- small-motor potentials of short durationEchocardiography- valvular thickeningECG- arrhythmia

Dx: (Other Tests) Ischemic forearm test- metabolic myopathies

examines the metabolic pathways that provide energy for muscle function during anaerobic exercise Blood pressure cuff inflated above systolic pressure (forearm) Repetitively grasp an object (once or twice per second) for 2-3 minutes. Serum CK, ammonia, and lactate; urine myoglobin analysis --immediately obtained before

and 5 minutes, 10 minutes, and 20 minutes after inflating the cuff. Positive ischemic forearm test results may occur in patients with Tarui disease, Cori disease

(glycogen-storage disease type III), and McArdle disease (glycogen-storage disease type V).

Ischemic Forearm Test Interpretation

N= ↑ lactate levels (at least 5-10 mg/dL) N= ↑ ammonia levels (at least 100 mcg/dL) with return to baseline.

mitochondrial myopathy- ↑ lactate at restmyoadenylate deaminase deficiency-Failure of ammonia to increase with lactate is.

glycogen-storage disease-failure of lactate to increase with ammonia ( blockage of a carbohydrate metabolic pathway)

Dx: (Other Tests)Glucose or sucrose intake before exercise

Thirty minutes before an exercise test, a beverage containing 75 grams of sucrose is ingested or a glucose infusion of 6 ml per minute is begun.

Carbohydrate intake increases the symptoms of exercise intolerance in Tarui disease In contrast, carbohydrate decreases the symptoms of exercise intolerance in McArdle

disease (glycogen-storage disease type V) and has no effect on phosphoglycerate mutase deficiency

Dx: (Histologic Findings)An abnormal polysaccharide, unique to Tarui disease, may be found, especially in older patients- periodic acid-Schiff (PAS) positive but is not digested by diastase.

Tx:No specific medical treatment required Advise to avoid high-carbohydrate meals -may exacerbate the exercise intolerance.

Instruct to avoid vigorous exercise - may lead to myoglobinuria.

Regular renal function monitoring if with myoglobinuria.Monitor Hgab and RET countWOF: gallstones, renal failure

PHOSPHOGLYCERATE MUTASE (PGM) DEFICIENCY

type IX glycogenosis

PHOSPHOGLYCERATE KINASE (PGK) DEFICIENCY

type X glycogenosis

PGKcatalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate One molecule of adenosine triphosphate (ATP) is generated in the process.

PGK DEFICIENCY inborn error of metabolism inherited in an X-linked recessive manner

gene responsible is located on the X chromosome (Xq13)

PGK DEFICIENCY3 main features are

1. Hemolytic anemia

2. Intellectual disability

3. Muscle problems (myopathy).

An individual with the disorder may be affected by one or more of these features, but it is unusual for one person to exhibit all three signs

POSSIBLE CLINICAL FINDINGS Hemolytic anemia

Varying degrees of intellectual disability

Emotional lability

Motor or sensory aphasia

exercise-induced pain, stiffness, or cramps

Splenomegaly

Hemiplegia

X-linked genetic trait. In such cases, the disorder is fully expressed in males only; however, some

females who carry one copy of the disease gene (heterozygotes) may have hemolyticanemia.

TX Standard Therapies

Fe supplements and blood transfusions when needed

Avoidance of strenuous exercise

Bone marrow transplantation may be an option

Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Ongoing research on enzyme replacement therapies that will return a missing enzyme to the body

REFERENCES:Harrison’s Principles of Internal MedicineWebMDMedscape