What Neurological Disorders Can Be Inherited?

Hereditary neurological disorders are also known as hereditary neuropathies and are divided into 4 groups corresponding to the type of affected neurons:

• Hereditary motor and sensory neuropathies

These neuropathies (pathology of the nervous system) affect both sensory and motor neurons.

• Hereditary motor neuropathies

These neuropathies affect motor neurons.

• Hereditary sensory neuropathies

These neuropathies affect sensory neurons.

• Hereditary sensory and automatic neuropathies.

These neuropathies affect sensory nerve cells and the autonomic nervous system responsible for involuntary actions such as digestion and blood pressure.

There are more than 24 hereditary neurological disorders and here we provide an overview of some of them:

• Familial Alzheimer’s Disease
• Frontotemporal Dementia
• Familial Creutzfeldt-Jacob Disease
• Neurofibromatosis
• Tourette’s Syndrome
• Wilson Disease
• Huntington Disease
• Charcot-Marie-Tooth Disease
• Familial Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)
• Spinocerebellar Ataxias
• Multiple System Atrophy
• Olivopontocerebellar Atrophy
• Fragile X and Fragile X Associated Tremor Ataxia Syndrome (FXTAS)
• CADASIL
• Familial Dysautonomia
• Von Hippel-Lindau Disease
• MELAS Syndrome
• Hereditary Spastic Paraplegia
• Mucopolysaccharidosis
• Primary Lateral Sclerosis
• Gaucher Disease
• Niemann-Pick Disease
• Fabry Disease
• Leukodystrophy

1- Familial Alzheimer’s Disease

Familial Alzheimer’s disease is a degenerative disease of the brain that manifest with cognitive deficits such as [2]:

• Memory loss
• Inability to function in social environment
• lack of judgment.

It is caused by mutations in the genes APP, PSEN1, or PSEN2.

APP is a gene that encodes a protein known as amyloid-beta precursor protein found in the membranes of neurons.

PSEN1 is a gene that encodes a protein known as presenilin-1 involved in the production of amyloid-beta from the amyloid-beta precursor protein.

PSEN2 is a gene that encodes a protein known as presenilin-2 which is also involved in the production of amyloid-beta from the amyloid-beta precursor protein.

Mutations in APP, PSEN1, and PSEN2 increase the production and accumulation of amyloid-beta precursor protein in the brain resulting in amyloid-beta plaques responsible for the degeneration of neurons.

2- Frontotemporal Dementia

Frontotemporal dementia is a neurodegenerative disease affecting the frontal and temporal parts of the brain causing cognitive disorders [3].

The cognitive disorders manifest with symptoms such as:

• Distance from family
• Vulgar speech
• Screaming
• Incapacity to control emotions, behavior, and temperament
• Obsessive and compulsive tendency to buy things

Frontotemporal Dementia is due to mutations in the gene MAPT that encodes for a protein known as TAU.

Mutations in the gene MAPT results in increased production of TAU and its accumulation in neurons and glia leading to their death.

3- Familial Creutzfeldt-Jacob Disease

Familial Creutzfeldt-Jacob disease is a progressive neurodegenerative disease affecting the brain and causing cognitive disorders such as:

• Memory loss
• Changes in behavior
• Ataxia (uncoordinated movements)

The disease is due to the accumulation of a glycoprotein known as a prion, which functions in the brain are not well known [4].

4- Neurofibromatosis

Neurofibromatosis is characterized by the growth of tumors along nerves that cause the appearance of symptoms such as [5]:

• Small lumps on the skin
• Scoliosis (malformation of the spine)
• Loss of vision and/or hearing due to the compression of nerves by the tumors.

There are 3 types of neurofibromatosis (Type I, II, and III) depending on the mutated gene.

Mutations in the tumor suppressor gene (a gene that prevents tumor), NF1 results in Neurofibromatosis type I.

Mutations in the tumor suppressor gene NF2 result in Neurofibromatosis type I, while mutations in different genes on chromosome 22 lead to Neurofibromatosis type III, also known as schwannomatosis.

5- Tourette’s Syndrome

Tourette’s syndrome is a neurological disorder that affects certain regions of the brain and is characterized by the presence of tics such as:

• Blinking
• Clearing throat
• Grunting
• Facial movements

The tics are sudden and repetitive [6].

The genetic causes of Tourette’s Syndrome are unknown; however, some cases are associated with mutations in genes such as SLITRK1, CNTNAP2, and HDC.

SLITRK1 is a protein found in the membrane of neurons where it is involved in the regulation of synapses.

CNTNAP2 is a protein found in the membrane of the neurons where it plays a role in axons.

HDC is an enzyme involved in the function of the neurotransmitter histidine.

6- Wilson Disease

Wilson disease is a rare genetic disease characterized by the accumulation of copper in different parts of the body including the brain, causing the following symptoms  [7]:

Changes in personality and behavior

• Migraine
• Seizures
• Fatigue
• Anxiety, depression, and psychosis
• Ataxia

And other symptoms such as:

• Liver disease symptoms
• Tiredness
• Swollen legs
• Yellowish skin
• Kayser-Fleisher rings in the eye

This disease is due to mutations in the gene ATP7B involved in removing excess copper in the body.

7- Huntington Disease

Huntington Disease is a neurodegenerative disease that affects the brain causing the following symptoms [8]:

• Dementia
• Depression
• Difficulty focusing
• Involuntary movements
• Stumbling, and clumsiness

This disease is due to a mutation in the gene encoding for the protein huntingtin which expression in the brain is toxic to nerve cells.

8- Charcot-Marie-Tooth Disease (CMT)

Charcot-Marie-Tooth disease is characterized by damages to sensory nerves (sensory neuropathy) and muscles (motor neuropathy) resulting in a loss of sensation and muscle strength [9].

The symptoms include:

• Loss of muscle mass in lower legs (reduction in muscle mass) causing foot drop and deformity of the muscles and ligaments of the toe (hammer toe).

CMT is caused by mutations that produce or support the function of axons or myelin. More than half of the mutations affect the gene PMP22 that encodes a protein that is part of myelin.

9- Familial Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)

Familial Amyotrophic Lateral Sclerosis is characterized by damages to motor neurons resulting in symptoms [10] such as:

• Muscles twitching and weakening
• Cramps
• Difficulty shewing or swallowing
• Nasal speech

The disease is caused by mutations in the gene SOD1 which encodes an enzyme known as superoxide dismutase that binds copper and zinc to prevent the accumulation of superoxide radicals which can damage nerve cells.

10- Spinocerebellar Ataxias (SCA)

Spinocerebellar ataxias are a group of degenerative diseases that affect a part of the brain known as the cerebellum and which controls movement (motor control).

The symptoms of spinocerebellar ataxias are mainly characterized by:

• Loss of balance and movement coordination of the muscles, including those of the hands, legs, eyes, and the ones controlling speech.

There are at least 27 types of spinocerebellar ataxias that are caused by unknown and known mutations in different genes that encode proteins such as Ataxin-1, Ataxin-2, Ataxin-3, Ataxin-7, and others [11].

11- Multiple System Atrophy (MSA)

Multiple system atrophy is a degenerative disease that affects nerve cells (neurons) that control movement and the autonomic nervous system responsible of involuntary actions such as digestion and blood pressure [12].

This disease manifests with symptoms such as:

• Slow movement and stiffness of the body (Parkinsonism)
• Uncoordinated movement
• Fainting
• Difficulty of speech
• Orthostatic hypotension (drop of blood pressure when standing up or sitting up)
• Problems with bladder control

The cause of Multiple system atrophy appears to be due to the accumulation of alpha-synuclein in a type of brain cells known as oligodendrocytes which produce myelin.

12- Olivopontocerebellar Atrophy (OPCA)

Olivopontocerebellar atrophy degenerative disease that affects specific parts of the cerebellum which control movement [13]. Symptoms of this disease include:

• Clumsiness
• Falling without apparent reason
• Veering of midline during walk
• Problems with speech and swallowing
• Abnormal eye movements
• Muscle spasms

Although olivopontocerebellar atrophy is a genetic disease, the genes that cause this disease are unknown.

13- Fragile X and Fragile X Associated Tremor Ataxia Syndrome (FXTAS)

FXTAS is a degenerative disease that also affects the cerebellum of individuals over the age of 50 (Typically men) and that results in cognitive deficits, parkinsonism, and alterations in the autonomous nervous system responsible for involuntary actions such as digestion and blood pressure [14].

• Symptoms include:
• Anxiety and irritability
• Depression
• Ataxia (Uncoordinated movements)
• Parkinsonism (slow movement and stiffness of the body)
• Uncontrollable shaking or twitching movements (Tremor)

FXTAS is due to mutations in the gene FMR1 encodes a protein known as FMRP (Fragile X mental retardation protein) involved in synaptic plasticity.

14- CADASIL

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy) is a disease that affects vessels in the brain (cerebrovascular) causing their thickening which limits blood supply to the brain (Ischemia) [15].

• Symptoms of CADASIL include:
• Migraine
• Ischemic ischemia or strokes
• Mood disorders

 CADASIL is caused by a mutation in the gene NOTCH3 that controls the muscles of the vessels.

15- Niemann-Pick Disease

Niemann-Pick disease is a metabolic disorder characterized by the accumulation of lipids (fatty substances) in different cells of the body including the brain cells [16].

The accumulation of the lipids in the nerve cells of different parts of the brain can lead to the following symptoms:

• Ataxia
• Dementia
• Seizures
• Slurred speech
• Difficulty swallowing

Other symptoms are associated with alterations in other organs.

They are 3 types of Niemann-Pick disease: type A, B, and C.

Type A and type B are caused by mutations in the gene SMPD1 the encodes for a protein involved in the storage of lipids (sphingolipids) in the cells. The storage is mediated by organelles in the cells, known as Lysosomes.

Typ2 c is caused by mutations in the genes NPC1 and NPC2 which encode for a protein involved in the transport of lipids.

16- Gaucher Disease

Gaucher disease is also a metabolic disorder characterized by the accumulation of lipids (fatty substances) in different cells of the body including the brain cells [17].

The accumulation of the lipids in the nerve cells of different parts of the brain can lead to the following symptoms:

• Defects in cognition and olfaction (smell)
• Dementia
• Serious convulsions
• Mental retardation
• Muscle twitching
• Apnea
• Stiffness and rigidity of the body

Other symptoms are associated with alterations in other organs such as fatigue, anemia, abdominal pain, enlarged liver, and spleen.

They are 3 types of Gaucher disease: type I, II, and III.

It is caused by mutations in the gene encoding an enzyme involved in the breakdown of a type of lipids (glucocerebrosides) leading to their accumulation in the cells.

17- Fabry Disease

Fabry disease is also a metabolic disorder characterized by the accumulation of lipids (fatty substances) in different cells of the body including the brain cells [18].

• The main neurological symptoms of Fabry disease are associated with abdominal, stomach, and joints.

Other symptoms include anemia, arthritis, and lesions of the skin vessels.

Fabry disease is caused by mutations in the gene encoding an enzyme involved in the breakdown of a type of lipids (sphingolipids) leading to their accumulation in the cells.

18- Familial Dysautonomia

Familial Dysautonomia is a progressive disorder that affects nerve cells (neurons) of the autonomous nervous system resulting in the following symptoms:

• Abnormal posture
• Abnormal walking
• Difficulty swallowing
• Speech and movement problems
• Absence of tears
• Insensitivity to pain
• Pneumonia
• Vomiting

Familial Dysautonomia is caused by mutations in the gene IKBKAP which encodes a protein known as IKAP protein, involved in the transcription of genes [19].

19- Von-Hippel-Lindau Disease

Von Hippel-Lindau disease is a rare genetic disease characterized by the presence of benign tumors in many parts of the brain [20].

Symptoms of this disease include:

• Dizziness
• Headaches
• Unbalanced walking
• Weakness of the limb’s muscles
• Deafness of one ear
• Blood pressure

This disease is caused by mutations in the VHL gene that encodes for a tumor suppressor protein (prevents tumors in the cells) known as Von Hippel-Lindau tumor suppressor.

20- MELAS Syndrome

MELAS syndrome (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) is a degenerative disease that affects the nervous system and muscles [21].

The symptoms of this disease include:

• Muscle weakness on one side of the body
• Intellectual disability (mental retardation)
• Loss of hearing and vision
• Headaches
• Anorexia
• Vomiting
• Seizures

This disease is caused by mutations in the mitochondrial DNA that encodes enzymes necessary for the production of energy (ATP).

21- Hereditary Spastic Paraplegia

Hereditary spastic paraplegia is a progressive disease that affects motor neurons in the spinal cord resulting in the following symptoms:

• Ataxia
• Cognitive deficit
• Epilepsy
• Impaired vision
• Deafness
• Difficulty walking
• Abnormal posture

This disease is due to mutations in genes such as SPG4 and SPG5 that encode proteins involved in the transport of proteins, and lipids along the axons of neurons [22].

22- Mucopolysaccharidosis

Mucopolysaccharidosis is characterized by the accumulation of complex sugars known in the cells and tissues of the body including the brain mucopolysaccharides [23].

The symptoms of this disease include:

• Dwarfism
• Thick skin
• Thick lips
• Enlarged mouth and tongue
• Rough facial features
• Intellectual disability (mental retardation)

There are 7 types of mucopolysaccharidosis (type I, II, III, IV, VI, VII, IX)

This group of diseases is due to mutations in genes involved in the breakdown of mucopolysaccharides which accumulation damages the body cells.

23- Primary Lateral Sclerosis

Primary lateral sclerosis is a degenerative disease that affects motor neurons in the brain resulting in the following symptoms:

• Weakness in the legs
• Unbalance
• Muscle Stiffness
• Clumsiness
• Impaired speech
• Overresponsive reflexes

Although primary lateral sclerosis has a genetic cause, the genes involved are not well known [24].

24- Leukodystrophy

A leukodystrophy is a group of degenerative diseases that affect the white matter of the brain, spinal cord, and other nerves of the body [25]. It manifests with the following symptoms:

• Increased irritability and sensitivity
• Muscle rigidity
• Loss of hearing or vision

This group of diseases is due to mutations affecting the myelin sheath that protect neurons and is involved in neurons’ action potential.

Conclusion

Inherited neurological diseases are mainly debilitating disorders that result in severe effects on cognitive defects and reduced quality of life. Unfortunately, there is no standard treatment for these diseases and treatments are mostly supportive and symptomatic [26].