Cuillier, MD*, Alessandri JL**, Bideault J, MD^***, Rabenja A, MD^***

*   Department of Gynecology ** Department of Neonatology, Félix Guyon'Hospital, *** Department of Obstetrics, Hospital Intercommunal de Sain Benoit, Réunion Island, France.

Definition: Myopathies are neuromuscular disorders in which the primary symptom is muscle weakness due to dysfunction of muscle fiber. Other symptoms of myopathies include muscle cramps, stiffness and spasm. Myopathies can be inherited (such as the muscular dystrophies) or acquired (such as common muscle cramps). Myopathies are grouped as follows:

• Congenital myopathies: characterized by developmental delays in motor skills, skeletal and facial abnormalities. They are occasionally diagnosed at birth.
• Muscular dystrophies: characterized by progressive weakness in voluntary muscles. Sometimes it is evident at birth.
• Mitochondrial myopathies: cause by genetic abnormalities in mitochondria.
• Glycogen storage diseases of muscle: cause by mutations in genes controlling enzymes that metabolize glycogen and glucose (Pompe's, Andersen's and Cori's disease).
• Myoglobinurias: caused by disorders in the metabolism of a fuel (Myoglobin) necessary for muscle work (Mc Ardle, Tarui and DiMauro diseases).
• Dermatomyositis, Myositis ossificans, Familial periodic paralysis.

Nemaline myopathy is a disease characterized by the presence in the muscle fibers of rod bodies. Nemaline myopathy belongs to the group of congenital non progressive myopathies. Nemaline myopathy has been classified into four forms:

• Congenital non-progressive form
• Congenital rapidly fatal form
• Adult onset
• Asymptomatic form

Nemaline myopathy in the neonate is rarely described in the literature and its diagnosis is difficult to establish in the neonate and must be obtained by performing a muscle biopsy. We described a curious case, whose diagnosis was performed after birth. Antenatal ultrasound findings were really atypical. We think that our patient had the clinical characteristics of the second form.

Etymology: From the Greek name "thread".

History: Nemaline myopathy was first described in 1963. Few antenatal diagnosis have been described and the majority of cases were described as Fetal Akinesia deformation Sequence (FADS) or Arthrogryposis Multiplex Congenital (AMC)

Prevalence: Nemaline myopathy is one of the most benign myopathies in older children and adults, but may be rarely associated with early death in the neonate.

Pathogenesis: Nemaline myopathy is a rare myopathy clinically characterized by muscular hypotonia, proximal or generalized weakness, with occasional involvement of facial and neck muscles. The histological criteria for Nemaline myopathy is the presence of nemaline bodies in the muscle fibers, sometimes associated with rods. The rods are recognized on routine hematoxylin-eosin staining. With the Gomoro trichrome stain, rods produce a red color in contrast to the blue-green of the muscle fibers. With the phosphotungstic acid hematoxylin stain, rod shows blue-black structures against the pinkish background of the fibers. The rods are readily demonstrated on electron microscopy as dense structures, rectangular shape with a lattice pattern of consistent periodicity and in continuity with the Z-lines. The rod bodies are composed largely of -actin and actin. The rod bodies show characteristic periodicity in both longitudinal and transverse sections, with the same electron density as the Z-disc.

Sonographic findings: According to Jayawant and Sina (2004), if idiopathic hydramnios is identified in a mother and dysfunctional fetal swallowing is seen, three fetal neuromuscular disorders should be ruled out:

1. X-linked myotubular myopathy
2. Congenital myoptonic dystrophy
3. Congenital nemaline myopathy.

In nemaline myopathy, the evolution varies according to the disease. Even the symptoms varry according to the disease. According to Vardon et al (1997), most of the antenatal sign are:

• Diminished fetal movements during the last trimester
• Polyhydramnios
• Inability to visualize the stomach
• Arthrogryposis of hands and feet
• Clubfeet
• Multiple joint contractures with limited movements

In nemaline myopathy, the nasal sign we described in our case has not been described in the literature yet.

Case Report:

This is a 30-year-old woman referred to our unit at 32 weeks, due to polyhydramnios and uterine contraction. The maternal abdomen was slightly tense and the patient was complaining of discomfort, frequent contractions and difficulty to sleep. The previous scans at 13 and 22 weeks were normal. The nuchal translucency and triple test were both normal. There was no family history of genetics disorders, malformations or relevant obstetrical past history.

In our unit, the ultrasound examination at 32 weeks revealed polyhydramnios (amniotic fluid index = 38 cm). The fetal movements seemed decreased (confirmed by the mother). The following findings were also observed in the scan:

• Different segments of the umbilical cord were thickened
• There was a strange secretion near the nose and coming from the left nostril
• The mouth did not show movements during the ultrasound examination

No other malformations were seen. The umbilical Doppler showed absent diastolic flow. The uterine artery resistance was normal. In order to relief the patient, an decompression amniocentesis was programmed, but twelve hours after the scan, the patient underwent an emergency cesarean, because the fetus showed acute fetal distress.

After birth, the newborn could not swallow and had few respiratory movements. The newborn increasingly had apnea, bradycardia and a severe hypotonia. Despite subsequent respiratory treatment and antibiotics, the newborn showed progressive respiratory insufficiency due to hypoventilation and was therefore transferred to the neonatal intensive care unit. Physical examination revealed a hypotonic neonate without facial abnormalities. There were no limb abnormalities. A neurological examination revealed weak tendon reflexes. Chest radiography showed no abnormalities. No signs of infection and metabolic disease were found. They were no external anomalies.

The baby required nasal oxygen therapy and feeding assistance during all the neonatal hospitalization. Intubation was performed fourth times. The baby had a bronchial congestion. A tracheotomy was done. A gastrostomy was done at fourth month of life. An anti-reflux gastroplasty was performed.

At 10 months of life, the baby had no deglutition and he was still hypotonic. He began to have a peripheric motricity. He required constant oxygenation therapy (FI 30%). Cerebral transfontanellar sonography, CT, MRI (including brainstem) and EEG were normal. The baby and the parents electromyogram were normal. Steinert dystrophia was eliminated by DNA analysis.  The Prader Willi syndrome was also eliminated. The karyotype was normal (46 XY). Finally, a muscular biopsy was done and the enzymologic studies suggested Nemaline myopathy. The electronic microscopic study confirmed the diagnosis.

Note the strange secretion near the nose and coming from the mouth.

Note the cord cyst.

Left image: The umbilical artery with absent diastole flow. Right image: The uterine artery with normal flow.

Postnatal view. Note the secretion coming from the nose of the newborn.

Implications for target examinations: It is important during antenatal life, to perform a detailed fetal analysis to exclude another syndromes. The diagnosis of nemaline myopathies typically performed by a muscle biopsy. 

Differential diagnosis: The differential diagnosis include: idiopathic polyhydramnios, central nervous system anomaly, Steinert myotony,  Zellweger syndrome, Prader-Willi syndrome (revealed after birth by passive and active weakness with muscular strenght diminution), non-immune fetal hydrops.

Associated anomalies: The antenatal and postnatal findings must lead to a muscle biopsy which is the fundamental element to establish  the diagnosis of nemaline myopathy.

Prognosis: Progression of Nemaline myopathy varies according to the type of disease. Among the different nosological forms of Nemaline myopathy, one morphological variant is marked by intranuclear rods in addition to sarcoplasmic rods. Such patients are include in two categories:
1. Adults
2. Young infants suffering from severe form. So intranuclear rods indicate unfavorable prognosis.

Recurrence risk: The mode of inheritance differs in the literature. Nemaline myopathy is thought to be a hereditary disease, and the mode of inheritance is heterogeneous, either dominant or recessive, with many loci and therefore various disorders. According to different authors, there is:

• NM1:  Autosomal dominant form with variable penetrance of the gene. This form has been observed with the mild Nemaline myopathy found in older children or adults.
• NM2:   Autosomal recessive form. The fatal neonatal Nemaline myopathy is probably due to a recessive autosomal gene.

Management: There is no cure for Nemaline myopathy, so treatment is based on the symptoms. Excessive exertion, which may cause nausea, headache and weakness, should be avoided. The use of vitamins in those who have severe muscle weakness (adult form) can sometimes be quite helplful. Vitamin therapies include Riboflavin, Coenzyme Q, Vitamine C and K and Carnitine. Physical therapy may be beneficial because it may help to extent the range of movement of muscles. Genetic counseling is an important issue but unfortunately the risk of recurence can hardly be given as the mode of inheritance may not be known. The only advice for further pregnancies is to look for suspicious signs and to do serial scans.

Our case is a rare case of Nemaline myopathy with antenal classic ultrasound signs: polyhydramnios, decreased fetal movement and thick umbilical cord. Nevertheless, Nemaline myopathy is a very rare etiology of polyhydramnios and nowadays there is no specific antenatal diagnosis. Detection of polyhydramnios and this atypic sign, which was nasal secretion (sign we never seen described on the literature) must orientated about Nemaline myopathy diagnosis. Indeed actually Nemaline myopathy diagnosis is often a retrospective diagnosis, made through autopsy and muscle biopsy.

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