Fetal Hypotonia & Genetics

Fetal Hypotonia & Genetics

Fetal hypotonia (reduced fetal muscle tone and movement)
Wide spectrum of genetic and non-genetic disorders
May present as:
• Decreased fetal movements
• Persistent abnormal limb posturing
• Arthrogryposis multiplex congenita (multiple joint contractures)
• Polyhydramnios (due to impaired swallowing)
• Fixed flexion deformities
• Fetal akinesia deformation sequence (FADS)
• Thin musculature
• Pulmonary hypoplasia in severe cases

The genetic causes can be broadly divided into disorders affecting:
1. Central nervous system (brain and spinal cord)
2. Anterior horn cells
3. Peripheral nerves
4. Neuromuscular junction
5. Skeletal muscle
6. Connective tissue
7. Metabolic and mitochondrial pathways
8. Chromosomal and copy number disorders

Pathophysiology of Fetal Hypotonia
Normal fetal tone depends on intact:
• Cerebral cortex and basal ganglia
• Brainstem
• Spinal cord motor neurons
• Peripheral nerves
• Neuromuscular junction
• Muscle fibers
• Connective tissue and joints

Prenatal Ultrasound Clues
Common ultrasound findings include:
• Decreased or absent fetal movements
• Arthrogryposis
• Clubfeet
• Camptodactyly
• Polyhydramnios
• Micrognathia
• Thin chest
• Pulmonary hypoplasia
• Growth restriction
• Hydrops fetalis
• Scoliosis
• Pterygia

Major Genetic Categories
Chromosomal Disorders
• Trisomy 18, Trisomy 13
• Down syndrome
• Wolf-Hirschhorn syndrome, Prader-Willi syndrome, Pallister-Killian syndrome

Fetal Akinesia Deformation Sequence (FADS)
A severe end phenotype characterized by absent fetal movement.
Key genes: MUSK, DOK7, RAPSN, CHRNG, CNTN1, PIEZO2, SYNE1, GLE1, CNTNAP1, ADCY6
• Associated syndromes:
• Multiple pterygium syndrome
• Lethal congenital contracture syndrome

Anterior Horn Cell Disorders
Spinal muscular atrophy
• SMN1 deletion
• Reduced movements
• Arthrogryposis in severe type 0

Congenital Myopathies
Genes: RYR1, ACTA1, NEB, TPM2, TPM3, MYH3, TTN, KLHL40, CFL2,
• Prenatal features:
• Polyhydramnios
• Reduced movement
• Contractures

Representative disorders:
• Nemaline myopathy
• Central core disease
• Congenital fiber-type disproportion

Congenital Muscular Dystrophies
Genes: LAMA2, FKRP , POMT1, POMT2, FKTN, LARGE1
Disorders:
• Walker-Warburg syndrome
• Muscle-eye-brain disease

Neuromuscular Junction Disorders
Genes: RAPSN, DOK7, MUSK, CHRNE, CHAT
Disease:
• Congenital myasthenic syndromes

Peripheral Neuropathies
Genes: CNTNAP1, CNTN1, MPZ, PMP22, SCN11A
Disease examples:
• Congenital hypomyelinating neuropathy
Connective Tissue Disorders
• Ehlers-Danlos syndrome
• Loeys-Dietz syndrome
• Congenital contractural arachnodactyly

Metabolic and Mitochondrial Disorders
Genes: MTM1, PYGM, COQ genes, POLG, FBXL4
Disease examples:
• X-linked myotubular myopathy
• Mitochondrial disease

Central Nervous System Disorders
Genes: TUBA1A, LIS1 (PAFAH1B1), RELN, COL4A1, MED13L
Disorders:
• Lissencephaly
• Pontocerebellar hypoplasia
Single-Gene Disorders with Prenatal Hypotonia

Disorder	Gene	Mutation Type	Preferred Test
Spinal muscular atrophy	SMN1	Exon deletion	Targeted deletion assay
X-linked myotubular myopathy	MTM1	SNP/indel	Exome
Nemaline myopathy	ACTA1, NEB	SNP/indel/CNV	Exome
Congenital myasthenic syndrome	RAPSN, DOK7	SNP/indel	Exome
Escobar syndrome	CHRNG	SNP/indel	Exome
Distal arthrogryposis	PIEZO2	SNP/indel	Exome
Titinopathy	TTN	SNP/indel/CNV	Exome
RYR1 myopathy	RYR1	SNP/indel	Exome
Lethal congenital contracture syndrome	GLE1	SNP/indel	Exome