リゾメリック点状軟骨異形成タイプ3【AGPS】

2025.08.22

やさしいまとめ

This article explains RCDP3, an ultra-rare genetic condition that impacts bone growth, neurological development, and organ function. It provides clear, research-based information on its causes, key symptoms, testing, and current care approaches to support families, caregivers, and medical professionals.

遺伝子領域 | Implicated Genomic Region

AGPS

Rhizomelic Chondrodysplasia Punctata Type 3 (RCDP3)

Rhizomelic Chondrodysplasia Punctata Type 3, or RCDP3, is an extremely rare genetic disorder that affects bone growth, neurological development, eye health, and respiratory function. This guide explains the condition in clear, evidence-based language to help families, caregivers, and medical professionals better understand its causes, symptoms, diagnostic methods, management options, and long-term outlook.

Genetic and Molecular Basis

The AGPS Gene

RCDP3 is caused by mutations in the AGPS gene, located on the long arm of chromosome 2 at position 2q31.2. The AGPS gene provides instructions for producing the enzyme alkylglycerone phosphate synthase, which operates within small cell structures called peroxisomes.

Role of Plasmalogen

The AGPS enzyme is critical for synthesizing plasmalogens, a specialized class of lipids abundant in the brain, heart, and lungs. Plasmalogens help maintain the flexibility of cell membranes, support nerve cell function, and protect tissues from oxidative stress. Without functional AGPS, plasmalogen production is impaired, disrupting cell signaling and overall organ development.

Inheritance Pattern

RCDP3 follows an autosomal recessive inheritance pattern. This means a child must inherit two faulty copies of the AGPS gene, one from each parent, to develop the disorder. Carriers with only one mutated gene typically show no symptoms.

Overview of RCDP and Its Subtypes

Rhizomelic Chondrodysplasia Punctata (RCDP) refers to a group of peroxisomal disorders. In RCDP3, only the AGPS enzyme is dysfunctional, while the peroxisomes themselves remain structurally intact.

The hallmark features of RCDP3 include shortened bones in the upper arms and thighs (known as rhizomelia), distinctive facial features, congenital cataracts, intellectual disability, and variable levels of muscle stiffness.

There are five known types of RCDP. RCDP3 is the rarest, with only a handful of genetically confirmed cases worldwide.

Epidemiology

RCDP in general is extremely uncommon, with an estimated prevalence of 0.5 to 0.7 per 100,000 births. Among these cases, RCDP3 is rarer still, with fewer than 10 confirmed cases globally. Based on current genetic testing rates, fewer than one new case is expected annually across major regions such as the United States and the five largest European countries.

Pathophysiology

When the AGPS enzyme fails to function, plasmalogens are not produced at levels needed for healthy growth and development. This deficiency impairs cell membrane flexibility and disrupts critical processes such as nerve signaling and protection against oxidative damage. The lack of plasmalogen explains the multi-system effects of the disorder, including neurological, skeletal, and respiratory complications.

Symptoms

Classical RCDP3

The more severe, or classical, form typically presents shortly after birth with a consistent group of symptoms:

Bone abnormalities such as rhizomelia, stippled calcifications in bone ends, and spinal deformities
Distinctive facial features including a wide forehead, midfacial hypoplasia, widely spaced eyes, a small upturned nose, and low-set ears
Eye abnormalities such as congenital cataracts, strabismus, and involuntary eye movements (nystagmus)
Neurological symptoms including severe intellectual disability, seizures, and either low or increased muscle tone
Growth restriction with low birth weight and markedly short stature
Respiratory problems including recurrent pneumonia and, in many cases, respiratory failure
Cardiac involvement in some individuals, such as structural defects like Tetralogy of Fallot

Milder or Atypical Forms

Atypical RCDP3 presents with a broader spectrum of outcomes. Some individuals:

Achieve limited mobility, such as walking independently
Speak in simple words or short sentences
Experience joint contractures or scoliosis
Show neurodevelopmental disorders, including ADHD, autism spectrum traits, or anxiety disorders
Live into adolescence or adulthood, though with ongoing health challenges

Diagnosis

Biochemical Tests

Markedly reduced or absent plasmalogen levels in red blood cells in classical cases; low but measurable levels in milder cases
Elevated phytanic acid levels, indicating disrupted lipid metabolism
Normal or mildly elevated levels of very long chain fatty acids (VLCFAs)

Imaging and Clinical Evaluation

X-rays showing rhizomelia and stippled bone calcifications
MRI scans detecting white matter abnormalities or brain atrophy
Ultrasound to assess hip dislocation
Echocardiograms to evaluate for heart defects

Genetic Testing

A definitive diagnosis relies on genetic sequencing to detect AGPS mutations. Techniques such as Sanger sequencing or whole exome sequencing are used. Carrier testing is recommended for parents and close family members to guide genetic counseling.

Management and Treatment

Current Approaches

There is no cure for RCDP3. Management focuses on treating symptoms and maintaining the best possible quality of life.

Multidisciplinary Care

Ophthalmology: Early cataract surgery to preserve vision
Orthopedics and Rehabilitation: Surgery and physical therapy to address joint limitations and mobility
Neurology: Anti-epileptic medication for seizure control, along with targeted physical therapy
Respiratory Support: Preventive measures for infections, supplemental oxygen, or mechanical ventilation when needed
Nutritional Support: Assistance with feeding difficulties and tailored growth support plans
Behavioral and Educational Support: Therapy for developmental disorders and medications such as gabapentin or guanfacine where appropriate
Genetic Counseling: Information for families regarding inheritance, prognosis, and reproductive options

Prognosis

Severe or Classical RCDP3

Children with classical RCDP3 often experience significant health complications and typically do not survive beyond the first decade of life, with respiratory infections and related complications being the most common causes of death.

Milder RCDP3

Individuals with less severe mutations, or those retaining some plasmalogen activity, may survive into adolescence or adulthood. Some achieve limited speech and independent movement. However, prognosis varies and does not always correlate with the degree of plasmalogen deficiency. Environmental and additional genetic factors may influence outcomes.

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キーワード｜Keywords

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