Tarui DiseaseEdit

Tarui disease, also known as glycogen storage disease type VII (GSD VII), is a rare metabolic myopathy caused by deficiency of the muscle isoform of the enzyme phosphofructokinase (PFK-M). The condition arises when mutations in the PFKM gene impair glycolysis in skeletal muscle, particularly during anaerobic exercise, leading to impaired energy production, exercise intolerance, and muscular symptoms. In some patients, a concurrent deficiency of phosphofructokinase in erythrocytes can occur, contributing to a hemolytic component. The disorder is inherited in an autosomal recessive pattern, which means that affected individuals typically have two copies of a PFKM-associated variant, one from each parent.

Tarui disease was first described in the 1960s by researchers led by Shiro Tarui in Japanese patients. Since then, clinicians have recognized its presentation across diverse populations, though the condition remains exceedingly rare. The classification as a distinct glycogen storage disease reflects its underlying defect in glycolytic flux within muscle, with diagnostic and therapeutic implications that distinguish it from other glycogen-related myopathies.

Overview

GSD VII is a form of a broader group of disorders known as glycogen storage diseasess. It is specifically tied to impaired glycolysis in muscle due to defective PFK activity.
The PFKM gene encodes the muscle-specific isoform of phosphofructokinase, an enzyme that catalyzes a key step in glycolysis. Mutations in PFKM reduce or abolish PFK-M activity in muscle, and sometimes in red blood cells. PFKM and phosphofructokinase are central to understanding the disease mechanism.
Clinically, Tarui disease presents as exercise intolerance with muscle cramps, weakness after physical activity, and frequently myoglobinuria (dark urine) following strenuous exercise. The condition can be episodic and may be triggered by illness, dehydration, or fasting.
Diagnosis relies on a combination of history, muscle biopsy findings, enzymatic testing, and genetic confirmation. Muscle tissue often shows high glycogen content, while PFK activity is reduced. Genetic testing commonly identifies disease-associated variants in the PFKM.
There is no widely available cure; management focuses on minimizing episodes, preserving muscle function, and reducing the risk of rhabdomyolysis through dietary and activity adjustments. Ongoing research explores potential future therapies, including gene-targeted approaches.

Signs and symptoms

Exercise intolerance beginning in childhood or adolescence, with disproportionate fatigue relative to effort.
Muscle cramps and progressive weakness after sustained or high-intensity activity.
Myoglobinuria following strenuous exercise, which can cause darkened urine and, in some cases, acute kidney stress if episodes are frequent.
Relatively normal resting muscle strength between episodes, with episodes often resolving with rest.
In some individuals, mild hemolytic features if erythrocyte PFK activity is affected, contributing to fatigue and anemia-related symptoms.

These features overlap with other glycogen storage diseases such as McArdle disease and can complicate the clinical picture, making genetic and enzymatic testing important for a precise diagnosis.

Genetics

Pattern: autosomal recessive inheritance. Affected individuals typically inherit one pathogenic PFKM variant from each parent.
Gene: the disease is linked to mutations in the PFKM, which encodes the muscle isoform of phosphofructokinase. The enzyme normally catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate in glycolysis, a rate-limiting step for ATP generation in working muscle.
Population considerations: while reported cases are scattered across populations, the extreme rarity of GSD VII means that many aspects of population prevalence remain unclear. Genetic counseling is advised for families affected by the condition.

Pathophysiology

Core defect: deficiency of PFK-M disrupts glycolysis in skeletal muscle, limiting rapid ATP production during anaerobic metabolism.
Metabolic consequences: impaired glycolytic flux reduces energy availability during exercise, leading to early fatigue, cramps, and susceptibility to exercise-induced muscle injury. Excess glycogen accumulates within muscle fibers, even though the glycogen structure remains largely normal.
Red blood cell involvement: in some patients, PFK deficiency is present in erythrocytes as well, contributing to a non-spherocytic hemolytic component that can complicate the clinical picture.
Biochemical parallels: the condition highlights how critical glycolysis is for muscle performance and how specific enzyme defects can produce myopathic symptoms despite normal resting muscle histology.

Diagnosis

Clinical suspicion arises from the characteristic exercise intolerance with myoglobinuria and episodic weakness after activity.
Laboratory and tissue testing: a muscle biopsy may show increased glycogen content in muscle fibers with relatively normal cell structure; a direct assay of PFK activity in muscle tissue reveals reduced activity. Blood lactate levels during exercise may rise less than expected, reflecting impaired glycolysis.
Genetic confirmation: sequencing of the PFKM gene identifies disease-associated variants, providing a definitive diagnosis and enabling carrier testing for relatives.
Differential diagnosis: conditions such as McArdle disease, Pompe disease, and other metabolic myopathies share features with Tarui disease and require distinct diagnostic approaches.

Management

No disease-modifying therapy is currently proven to cure Tarui disease. Care focuses on reducing risk and managing symptoms.
Diet and hydration: avoiding prolonged fasting and ensuring regular carbohydrate intake around physical activity can help maintain energy substrates and reduce the likelihood of symptomatic episodes.
Exercise management: tailored, moderate-intensity, endurance-type training under medical supervision may help preserve muscle function and delay deconditioning, while avoiding high-intensity or prolonged exertion that precipitates symptoms.
Monitoring and support: routine assessment of kidney function during episodes of myoglobinuria, education for patients and families, and genetic counseling are standard components of care.
Experimental approaches: research into targeted therapies, including gene-based strategies and other metabolic interventions, is ongoing, but no established gene therapy or pharmacologic treatment is widely available at this time.

Epidemiology

Tarui disease is exceedingly rare, with a small number of documented cases worldwide. Estimated prevalence is not well defined due to underdiagnosis, variable reporting, and the rarity of the condition.
The rarity contributes to uncertainties about natural history, full spectrum of mutations, and long-term outcomes, underscoring the value of specialized metabolic clinics and collaborative research networks.

History

The condition is named after Shiro Tarui, who and colleagues described the disorder in the mid-20th century in Japan as part of the expanding catalog of inherited glycogen storage diseases.
Over time, the recognition of Tarui disease as GSD VII helped unify clinical, biochemical, and genetic observations under a single diagnostic framework.