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Achalasia Microcephaly


Achalasia Microcephaly syndrome is a rare condition whereby achalasia in the oesophagus manifests alongside microcephaly and mental retardation. This is a rare constellation of symptoms with a predicted familial trend.

The main signs of achalasia microcephaly syndrome involve the manifestation of each individual disease associated with the condition. Microcephaly can be primary, where the brain fails to develop properly during pregnancy, or secondary, where the brain is normal sized at birth but fails to grow as the child ages. Abnormalities will be observed progressively after birth whereby the child will display stunted growth and physical and cognitive development. The occipital-frontal circumference will be at or near the extreme lower end, the third percentile, indicating microcephaly. There are both genetic and behavioural causes of microcephaly.

Achalasia, or oesophageal achalasia, is a disorder occurring in the lower oesophageal sphincter (LES). The LES fails to relax completely, resulting in frequent vomiting and regurgitation, usually one to two hours after meals. If untreated, the long-term health of the individual will be compromised, leading to the development of dysphagia, weight loss and chronic aspiration. It is very rare in children, especially siblings. Mortality, especially in young children, can occur.

As of 2017, there are 5 reported cases of achalasia microcephaly syndrome, all of which involve children.

Signs and Symptoms
The main symptoms of achalasia microcephaly syndrome are the progressive manifestation of the major symptoms associated with the individual diseases, in young children.

Achalasia causes dysphagia, which leads to difficulties when eating, frequent vomiting after meals and possible respiratory arrest due to chronic aspiration. Symptoms can manifest at ages as young as six weeks.

Alongside prominent dysphagia, the child will have microcephaly, which is characterised by an abnormally small head. Mild scaphocephaly may also be observed. This can manifest upon or after birth. Slow cognitive and fine motor development as well as delayed speech will be observed. Craniofacial dysmorphism, such as a globular-shaped nose, micrognathia and a flattened forehead may also be involved, but is not observed in all cases. Camptodactyly of some fingers can also manifest.

Etiology
Achalasia microcephaly has only been reported in children, despite achalasia being associated as an adult disease.

The first case involved an affected family of four children, three sisters and one brother, from northwest Mexico. All three sisters underwent the Heller procedure in order to relieve vomiting and regurgitation due to achalasia. The brother passed away at four and a half years old, due to the improper diagnosis of recurrent vomiting and resultant malnourishment. All siblings had slow to moderate cognitive development within the mentally retarded criteria. Both parents were unaffected and were from the same small village.

The second case involved two affected brothers, aged seven and nine, from Libya, in a family of six children. By the age of two, both children were vomiting and regurgitating recurrently, had slow development and suffered from pneumonitis. They also displayed mild micrognathia and scaphocephaly. The elder son underwent a modified Heller’s operation at age six. Their parents were first cousins, however, chromosomal studies did not observe any abnormalities.

The third examined case was an affected nine-year-old boy born to unaffected parents who were from the same north-western Mexican area as the first reported case. It is denied but implicated that the parents were closely related. Abnormalities in motor function, physical appearance and difficulties during feeding manifested after birth. By eight months, psychomotor retardation was prominent and at nine months, malnourishment was extreme and so oesophagomyotomy (Heller myotomy) was performed. At eighteen months, microcephaly was revealed.

The fourth case study involved an affected German child. Unlike previous cases, the condition was attributed to the anti-malaria drug, Mefloquine, which was prescribed during pregnancy. There is no apparent genetic correlation between parents. At eight weeks, the child was officially diagnosed with microcephaly and displayed craniofacial dysmorphism and muscular hypotonia similar to previous cases. Vomiting, seizures and respiratory arrest were common. It was noted that only 5.4% of pregnancies under the medication of Mefloquine experienced abnormalities. This is the first case involving a person of European descent.

The fifth, most recent case, involved a girl born to consanguineous parents from Pakistan. There was  no history of abnormalities or genetic disorders in previous children in the family. Gestational diabetes during the pregnancy did not cause any significant complications. Feeding difficulties and recurrent vomiting began to occur at six weeks, resulting in severe weight loss. The girl received surgery and repeated balloon dilatations by the age of two for severe achalasia. She was diagnosed with microcephaly at age six after concerns for her delayed fine motor skills and limited understanding of speech.

Mechanism
Achalasia is a neurodegenerative disease characterised by the degeneration of neurones of the myenteric plexus which are responsible for the motility of the digestive tract. It is extremely rare in children and normally affects the lower oesophageal sphincter (LES). LES contraction prevents acid reflux while relaxation allows food to enter the stomach. Impaired LES relaxation therefore leads to dysphagia, as the oesophagus cannot be emptied. Familial achalasia, whereby achalasia manifests among siblings, is noted in families displaying consanguinity or inbreeding as the disease can be passed on as an autosomal recessive trait.

Microcephaly can manifest due to a variety of reasons, these include: TORCH infections, chromosomal and biochemical abnormalities and can be transmitted as an autosomal recessive, dominant or X-linked disorder. It is most commonly caused by congenital infections due to viruses such as cytomegalovirus, herpes simplex virus and Zika virus. The severe reduction of neural progenitors and neurones as a result of cell cycle arrest and neural progenitor death due to viral infection leads to microcephaly. There are two types of microcephaly, primary, occurring before thirty-two weeks of gestation or secondary, after birth. A reduced production of neurones is attributed to primary microcephaly whilst decreased dendritic connection is thought to cause secondary microcephaly, all amounting to an estimated brain size that is significantly smaller than average. Further, the cerebral cortex occupies 55% of the human brain, therefore, most microcephalic people are mentally retarded. .

Like familial achalasia, microcephaly has an autosomal recessive predisposition.

Although no disease-causing gene has been identified, studies suggest that due to the consanguinity or close relatedness of parents observed in four out of five cases, achalasia microcephaly might be inherited via an autosomal recessive gene.

Diagnosis
Symptoms of achalasia can be detected by fluoroscopy during barium swallow or oesophageal manometry.

Barium Swallow
A positive barium swallow with display aperistalsis, minimal LES opening and oesophageal dilation as the main indicator of the disease.

Oesophageal Manometry
Patients who suffer from the vigorous achalasia variant of the disease, do not express dilation. Manometry is the best, most sensitive method in these cases as it can diagnose abnormalities related to achalasia without dilation.

Microcephaly
Microcephaly is usually diagnosed after the onset of achalasia by eighteen months or older. An occipital-frontal head circumference of less than three standard deviations is an indication of microcephaly. Radiography and NMR imaging of the skull can also be utilised. A physical examination of height and weight proportions as well as IQ and motor development is implemented for further confirmation as not all children with microcephaly have abnormal development. A positive test will show normal to abnormal proportions, a low IQ and slow motor development.

Management
There is currently no treatment to reverse the neuropathology of achalasia or the effects of microcephaly.

Instead, treatment for achalasia symptoms focuses on the reduction of LES pressure to relieve dysphagia and therefore prevent further regurgitation, vomiting and aspiration. These include drugs such as anticholinergics, mechanical dilation with a balloon dilator, or heller myotomy surgery.

Exogenous growth hormones can be used to boost development in microcephalic patients.

Research
No disease causing gene for achalasia microcephaly has been found, however candidate genes for research include genes that are known to be associated with the individual diseases that manifest alongside achalasia. Studies implicate that biological disturbances in the pathways downstream of these candidate genes can lead to the development of achalasia.

It is suggested that the disease has roots in neurological dysfunction due to the co-occurrence of microcephaly, the progressive narrowing of the oesophagus in the early stages of life and intellectual disability. Whole-exosome and whole-genome sequencing is proposed for the discovery of the underlying genetic cause of achalasia microcephaly.

The familial trend of disease manifestation between siblings along with consanguinity in majority of cases is consistent with an autosomal recessive inheritance.