Onset : Early childhood

Progression: Chronic progressive

Clinical: Cerebellar ataxia plus syndrome / Optic Atrophy Plus Syndrome

Ocular: Optic atrophy, nystagmus, scotoma, and bilateral retrobulbar neuritis.

Other: Mental retardation, myoclonic epilepsy, spasticity, and posterior column sensory loss. Tremor in some cases.

Musculoskeletal

Contractures, lower limbs, Achilles tendon contractures, Hamstring contractures, Adductor longus contractures

Systemic

Hypogonadotrophic hypogonadism.

Behr syndrome is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay.

Although it is an autosomal recessive disorder, heterozygotes may still manifest much attenuated symptoms. Autosomal dominant inheritance also being reported in a family. Recently a variant of OPA1 mutation with phenotypic presentation like Behr syndrome is also described. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder.

BVVL is marked by a number of cranial nerve palsies, including those of the motor components involving the 7th and 9th-12th cranial nerves, spinal motor nerves, and upper motor neurons. Major features of BVVL include facial and neck weakness, fasciculation of the tongue, and neurological disorders from the cranial nerves. The neurological manifestations develop insidiously: they usually begin with sensorineural deafness, progress inexorably to paralysis, and often culminate in respiratory failure. Most mortality in patients has been from either respiratory infections or respiratory muscle paralysis. Pathological descriptions of BVVL include injury and depletion of 3rd-7th cranial nerves, loss of the spinal anterior horn cells, degeneration of Purkinje cells, as well as degeneration of the spinocerebellar and pyramidal tracts. The first symptoms in nearly all cases of BVVL is progressive vision loss and deafness, and the first initial symptoms are seen anywhere from one to three years.

Most cases of deafness are followed by a latent period that can extend anywhere from weeks to years, and this time is usually marked by cranial nerve degeneration. Neurological symptoms of BVVL include optic atrophy, cerebellar ataxia, retinitis pigmentosa, epilepsy and autonomic dysfunction. Non-neurological symptoms can include diabetes, auditory hallucinations, respiratory difficulties, color blindness, and hypertension.

The age of onset is in a child's infancy. Bilateral corneal opacification started in the second year of life and led to severe visual impairment. However, cornea surgery and replacement resulted in better vision.

Symptoms include a combination of spinocerebellar degeneration and corneal dystrophy. Mental retardation and slowly progressive cerebellar abnormalities were also diagnosed in patients. Other symptoms include corneal edema, thickening of Descemet membrane, and degenerative pannus. Abnormalities were found in muscle and sural nerves.

Symptoms typically are onset in the adult years, although, childhood cases have also been observed. Common symptoms include a loss of coordination which is often seen in walking, and slurred speech. ADCA primarily affects the cerebellum, as well as, the spinal cord. Some signs and symptoms are:

Autosomal recessive cerebellar ataxia type 1 (ARCA1) is a condition characterized by progressive problems with movement. Signs and symptoms of the disorder first appear in early to mid-adulthood. People with this condition initially experience impaired speech (dysarthria), problems with coordination and balance (ataxia), or both. They may also have difficulty with movements that involve judging distance or scale (dysmetria). Other features of ARCA1 include abnormal eye movements (nystagmus) and problems following the movements of objects with their eyes. The movement problems are slowly progressive, often resulting in the need for a cane, walker, or wheelchair.

The combination of muscular hypotonia and fixed dilated pupils in infancy is suspicious of Gillespie syndrome. Early onset partial aniridia, cerebellar ataxia, and mental retardation are hallmark of syndrome. The iris abnormality is specific and seems pathognomonic of Gillespie syndrome. The aniridia consisting of a superior coloboma and inferior iris hypoplasia, foveomacular dysplasia.

Atypical Gillespie syndrome associated with bilateral ptosis, exotropia, correctopia, iris hypoplasia, anterior capsular lens opacities, foveal hypoplasia, retinal vascular tortuosity, and retinal hypopigmentation.

Neurological signs ar nystagmus, mild craniofacial asymmetry, axial hypotonia, developmental delay, and mild mental retardation. Mariën P did not support the prevailing view of a global mental retardation as a cardinal feature of Gillespie syndrome but primarily reflect cerebellar induced neurobehavioral dysfunctions following disruption of the cerebrocerebellar anatomical circuitry that closely resembles the "cerebellar cognitive and affective syndrome" (CeCAS).

Congenital pulmonary stenosis and helix dysplasia can be associated.

Non-progressive congenital ataxia (NPCA) is a non-progressive form of cerebellar ataxia which can occur with or without cerebellar hypoplasia.

Neuroimaging like MRI is important. However, there was considerable intrafamilial variability regarding neuroimaging, with some individuals showing normal MRI findings. Early individual prognosis of such autosomal recessive cerebellar ataxias is not possible from early developmental milestones, neurological signs, or neuroimaging.

Most cases of autosomal recessive cerebellar ataxia are early onset, usually around the age of 20. People with this type of ataxia share many characteristic symptoms including:

- frequent falls due to poor balance

- imprecise hand coordination

- postural or kinetic tremor of extremities or trunk

- dysarthria

- dysphasia

- vertigo

- diplopia

- lower extremity tendon reflexes

- dysmetria

- minor abnormalities in ocular saccades

- attention defects

- impaired verbal working memory and visuospatial skills

- Normal life expectancy

Autosomal recessive ataxias are generally associated with a loss of proprioception and vibration sense. Arreflexia is more common in autosomal recessive ataxia than autosomal dominant ataxias. Also, they tend to have more involvement outside of the nervous system. Mutations in subunit of the mitochondrial DNA polymerase (POLG) have been found to be a potential cause of autosomal recessive cerebellar ataxia.

Classification systems for malformations of the cerebellum are varied and are constantly being revised as greater understanding of the underlying genetics and embryology of the disorders is uncovered. A classification proposed by Patel S in 2002 divides cerebellar malformations in two broad groups; those with cerebellar hypoplasia and; those with cerebellar dysplasia.

- I. Cerebellar hypoplasia

- A. Focal hypoplasia

- 1. Isolated vermis

- 2. One hemisphere hypoplasia

- B. Generalized hypoplasia

- 1. With enlarged fourth ventricle (“cyst,”), Dandy-Walker continuum

- 2. Normal fourth ventricle (no “cyst”)

- a. With normal pons

- b. With small pons i. Normal foliation

- a) Pontocerebellar hypoplasias of Barth, types I and II

- b) Cerebellar hypoplasias, not otherwise specified

Brown-Vialetto-Van-Laere syndrome (BVVL), sometimes known as Brown's Syndrome, is a rare degenerative disorder often initially characterized by progressive sensorineural deafness.

The syndrome most often affects children, adolescents, and young adults. As knowledge of BVVL grows some adult patients have now been diagnosed. There is no known cure, however with prompt treatment the prognosis may be positive with some patients stabilizing and even minor improvements noted in certain cases.

Non-progressive early onset ataxia and poor motor learning are the commonest presentation.

Pontocerebellar hypoplasia is classified as follows:

Pontine and cerebellar hypoplasia is also observed in certain phenotypes of X-linked mental retardation – so called MICPCH.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders caused by genetic mutations and characterised by progressive atrophy of various parts of the brain such as the cerebellum or brainstem (particularly the pons). Where known, these disorders are inherited in an autosomal recessive fashion. There is no known cure for PCH.

Autosomal dominant cerebellar ataxia (ADCA) is a form of spinocerebellar ataxia inherited in an autosomal dominant manner. ADCA is a genetically inherited condition that causes deterioration of the nervous system leading to disorder and a decrease or loss of function to regions of the body.

Degeneration occurs at the cellular level and in certain subtypes results in cellular death. Cellular death or dysfunction causes a break or faulty signal in the line of communication from the central nervous system to target muscles in the body. When there is impaired communication or a lack of communication entirely, the muscles in the body do not function correctly. Muscle control complications can be observed in multiple balance, speech, and motor or movement impairment symptoms. ADCA is divided into three types and further subdivided into subtypes known as SCAs (spinocerebellar ataxias).

Corneal-cerebellar syndrome (also known as Der Kaloustian-Jarudi-Khoury syndrome) is an autosomally resessive disease that was first described in 1985. Three cases are known: all are sisters in the same family.

Harding ataxia, also known as Early onset cerebellar ataxia with retained reflexes (EOCARR), is an autosomal recessive cerebellar ataxia originally described by Harding in 1981. This form of cerebellar ataxia is similar to Friedreich ataxia including that it results in poor reflexes and balance, but differs in several ways, including the absence of diabetes mellitus, optic atrophy, cardiomyopathy, skeletal abnormalities, and the fact that tendon reflexes in the arms and knees remain intact. This form of ataxia is characterized by onset in the first 20 years, and is less severe than Friedreich ataxia. Additional cases were diagnosed in 1989, 1990, 1991, and 1998.

Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency. is a rare genetic disorder. The disorder is characterized by partial aniridia (meaning that part of the iris is missing), ataxia (motor and coordination problems), and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.

Symptoms of cerebellar abiotrophy include ataxia or lack of balance, an awkward wide-legged stance, a head tremor (intention tremor) (in dogs, body tremors also occur), hyperreactivity, lack of menace reflex, stiff or high-stepping gait, coarse or jerky head bob when in motion (or in very young animals, when attempting to nurse), apparent lack of awareness of where the feet are (sometimes standing or trying to walk with a foot knuckled over), poor depth perception, and a general inability to determine space and distance. The symptoms, when taken as a group, are distinctive and not easily mimicked by other illnesses, though certain types of neurological injury and infection need to be ruled out. Verifying the diagnosis in a laboratory setting is possible only by examining the brain post-mortem to determine if there has been a loss of Purkinje cells.

Most affected animals have normal intelligence and mildly affected animals can, in theory, live out a normal lifespan. However, affected animals are quite accident-prone, and for this reason many animals that develop CA, particularly horses, are euthanized for humane reasons. Horses may experience difficulty stepping up and over objects, run into fences, fall easily, and even if allowed to mature to full growth, are generally considered unsafe to ride. Dogs may need lifetime assistance with tasks such as climbing stairs.

In horses, the symptoms may worsen from the time of onset for six to 12 months, but if not severe enough to mandate euthansia, they stabilize over time. In some dog breeds, symptoms appear to progressively worsen, but research is not consistent on this point. There also is some evidence that affected animals partially compensate for the condition by cognitively learning alternative methods for moving or to determine distance, and thus appear to improve because they become less accident-prone.

Spinocerebellar ataxia (SCA) is one of a group of genetic disorders characterized by slowly progressive incoordination of gait and is often associated with poor coordination of hands, speech, and eye movements. A review of different clinical features among SCA subtypes was recently published describing the frequency of non-cerebellar features, like parkinsonism, chorea, pyramidalism, cognitive impairment, peripheral neuropathy, seizures, among others. As with other forms of ataxia, SCA frequently results in atrophy of the cerebellum, loss of fine coordination of muscle movements leading to unsteady and clumsy motion, and other symptoms.

The symptoms of an ataxia vary with the specific type and with the individual patient. In general, a person with ataxia retains full mental capacity but progressively loses physical control.

OPCA is characterized by progressive cerebellar ataxia, leading to clumsiness in body movements, veering from midline when walking, wide-based stance, and falls without signs of paralysis or weakness. Clinical presentation can vary greatly between patients, but mostly affects speech, balance and walking. Other possible neurological problems include spasmodic dysphonia, hypertonia, hyperreflexia, rigidity, dysarthria, dysphagia and neck dystonic posture.

The syndrome causes cerebellar ataxia (balance and coordination problems), mental retardation, congenital cataracts in early childhood, muscle weakness, inability to chew food, thin brittle fingernails, and sparse hair.

Small stature, mild to severe mental retardation and dysarthria (slow, imprecise speech) are usually present.

Various skeletal abnormalities (e.g., curvature of the spine) and hypergonadotropic hypogonadism often occur.

Muscle weakness is progressive, but life expectancy is near normal.

Usually symptoms of cerebellar hypoplasia can be seen immediately at birth in cats, but sometimes can take two months or so to become apparent in dogs. Cerebellar hypoplasia causes jerky movements, tremors and generally uncoordinated motion. The animal often falls down and has trouble walking. Tremors increase when the animal is excited and subside when at ease.

Aniridia is the absence of the iris, usually involving both eyes. It can be congenital or caused by a penetrant injury. Isolated aniridia is a congenital disorder which is not limited to a defect in iris development, but is a panocular condition with macular and optic nerve hypoplasia, cataract, and corneal changes. Vision may be severely compromised and the disorder is frequently associated with a number of ocular complications: nystagmus, amblyopia, buphthalmos, and cataract. Aniridia in some individuals occurs as part of a syndrome, such as WAGR syndrome (kidney nephroblastoma (Wilms tumour), genitourinary anomalies and intellectual disability), or Gillespie syndrome (cerebellar ataxia).