Arakawa's syndrome II

Overview

Arakawa’s Syndrome II is a rare inherited metabolic disorder classified under inborn errors of cobalamin (vitamin B12) metabolism. It is characterized by a functional deficiency in intracellular vitamin B12 processing, leading to combined elevations of methylmalonic acid (MMA) and homocysteine in the body. The condition affects multiple systems, including the hematologic, neurologic, and gastrointestinal systems.

It is also referred to as cobalamin C (cblC) disease, one of the most common disorders of vitamin B12 metabolism, and was first described by Tsuneo Arakawa and colleagues. Arakawa’s Syndrome II usually presents in infancy or early childhood, but later-onset forms have been documented.

Causes

Arakawa’s Syndrome II is caused by mutations in the MMACHC gene (methylmalonic aciduria and homocystinuria, cblC type), which is responsible for processing dietary vitamin B12 into its active forms:

• Methylcobalamin – needed for homocysteine metabolism

• Adenosylcobalamin – needed for the breakdown of certain amino acids and fatty acids

This is an autosomal recessive disorder, meaning two mutated copies (one from each parent) are required for the disease to manifest.

Symptoms

The symptoms of Arakawa’s Syndrome II can vary significantly depending on the age of onset, but typical features include:

Infantile/Early-Onset Form:

• Failure to thrive

• Feeding difficulties

• Developmental delays

• Hypotonia (reduced muscle tone)

• Seizures

• Megaloblastic anemia

• Hydrocephalus or cerebral atrophy

• Retinopathy or visual impairment

Late-Onset Form:

• Neuropsychiatric disturbances

• Progressive gait abnormalities or myelopathy

• Cognitive decline

• Vascular complications (e.g., thromboembolism)

Diagnosis

Diagnosis of Arakawa’s Syndrome II is based on clinical presentation, metabolic screening, and genetic testing. Steps include:

• Blood and urine tests: Elevated methylmalonic acid and homocysteine levels

• Complete blood count (CBC): May reveal macrocytic anemia

• Genetic testing: Confirms pathogenic variants in the MMACHC gene

• Newborn screening: In some countries, tandem mass spectrometry may detect elevated C3 acylcarnitine or MMA

Treatment

Treatment focuses on reducing toxic metabolite levels and managing symptoms. Main components include:

Pharmacologic Therapy:

• Hydroxycobalamin (vitamin B12): High-dose intramuscular injections are the mainstay of treatment

• Betaine: Helps reduce homocysteine levels by remethylation

• Folinic acid (leucovorin): Supports folate metabolism and homocysteine processing

• Carnitine: To support energy metabolism and reduce acylcarnitine accumulation

Supportive Care:

• Management of seizures, vision problems, or developmental delays

• Physical, occupational, and speech therapy as needed

• Nutritional support in infants with feeding difficulties

Prognosis

The prognosis of Arakawa’s Syndrome II varies depending on the severity and timing of diagnosis:

• Early-onset forms are often associated with more severe neurological and developmental impairments

• Late-onset forms may have a better outlook with early and consistent treatment

• Lifelong treatment and monitoring are required to prevent metabolic crises and manage complications

With early diagnosis and appropriate therapy, many patients can achieve developmental milestones and avoid severe organ damage, though residual impairments may persist.