Introduction

Carnosinemia, also known as carnosinuria, is an extremely rare inherited condition that causes a disruption in how the body uses and breaks down food into energy^. It is so rare that only 30 people have been reported in medical literature across the globe. 

People with this condition have low levels of an enzyme, known as carnosinase, which helps break down a small protein-like molecule called carnosine, in their blood.¹ As a result, they often have high amounts of carnosine in their urine and blood. The way this condition presents itself can be very different from person to person. Symptoms can appear quite early, in an infant aged 1-23 months. Despite that, some individuals may not have any noticeable symptoms, while others may experience serious problems like delays in developing, learning difficulties, weak muscle tone (hypotonia), seizures, and other brain-related issues.²

Causes of carnosinemia

Carnosinemia is known as a metabolic autosomal recessive disorder. When a condition is autosomal, it means you inherit a changed (mutated) gene. If you have an autosomal disorder, it means it was passed down to you from one or both of your parents who carry the mutated gene.

Autosomal disorders can be either dominant or recessive. In dominant disorders, just one mutated gene from one parent is enough to cause the condition. In recessive disorders, a person needs to inherit two copies of the mutated gene, one from each parent, in order to be affected.

In carnosinemia, it has been suggested that the mutated gene in question is carnosine dipeptidase 1 (CNDP1). The CNDP1 gene provides the instructions to produce carnosinase, which then helps break down carnosine as well as other dipeptides into amino acids. This is important, as your body breaks down the proteins you eat into dipeptides, and often breaking them down into amino acids is how your body processes protein, which is essential for various bodily functions such as:

• Provide energy
• Maintain healthy skin, hair, and nails
• Build strong muscles
• Strengthen your immune system
• Support proper digestion
• Regulate brain function

The body’s processing and distribution of nutrients, such as proteins, fats and carbohydrates into energy, is known as the metabolic process. If metabolic operations in the body are not working normally, this becomes a metabolic disorder. If genetic conditions are the cause of a metabolic disorder, this is known as an inborn error of metabolism. 

As protein is involved in a large part of normal metabolic functions, if the CNDP1 gene has been changed in a significant way (mutated) or is missing, it can disrupt the way the body processes protein. When healthy people experience protein deficiencies, they typically experience a weakened immune system, brittle bones and muscle loss. However, in patients with carnosinemia, these symptoms are much more severe, particularly as they are infants in the early stages of their development. The most notable of this alleged protein deficiency is hypotonia.

Hypotonia

Hypotonia is a condition of low muscle tone commonly found in babies. Muscle tone is important because it helps our bodies stay upright, like when sitting down or standing up. Muscle tone helps keep your body balanced by making sure your centre of gravity stays directly over your feet or other support. If you don’t have sufficient muscle tone, you will generally experience a lot of weakness and will struggle to hold up your limbs. When babies experience hypotonia, they appear quite floppy, almost like a rag doll when they are being held. 

There are many reasons why hypotonia happens in babies, as it can involve issues with muscles (muscle abnormalities), the connections between nerves and muscles (neuromuscular junctions) or the nerves themselves, including those in the brain and spinal cord (central and peripheral nervous systems). It may also be observed in inherited conditions, metabolic disorders, hormone-related problems, and both short-term and long-lasting illnesses.³

It is important to note that hypotonia in children is typically a symptom of another condition, it is very rare for children to be diagnosed only with hypotonia. Other conditions where hypotonia is a symptom include: Down’s syndrome, cerebral palsy, Prader-Willi syndrome, muscular dystrophy, as well as many others.

Hypotonia is often treated with various therapies, such as physical and occupational therapy to help improve motor skills. It often shows great improvement as they get older, as long as they maintain muscle tone. It is very common for children with hypotonia to have delayed development compared to children with normal muscle tone, especially when developing motor skills, which could lead to motor dysfunction.⁴ 

Motor dysfunction

There are two major groups of motor skills: gross motor skills and fine motor skills

Gross motor skills involve large muscle groups, such as our arms, legs and torso, to do things like walking, crawling and balancing.

Typical gross motor skills milestones:

• Sitting without support: 4-9 months
• Standing with support: 5-12 months
• Crawling on hands and knees: 5-13 months
• Walking with support: 6-14 months
• Standing without support: 6-17 months
• Walking without support: 7-18 months

Fine motor skills involve smaller muscle groups, like those in our fingers and hands, toes and feet, which are used for very precise movements like writing, buttoning a jumper or brushing your teeth.

Typical fine motor skills milestones: 

• Grasp reflex and controlling their hands: 0-3 months
• Reaching and grabbing objects: 3-6 months
• Pick up small objects: 6-9 months
• Precise picking up and scribble writing: 9-12 months
• Improved object handling, using cutlery and drawing: 12-24 months
• Controlled cutlery, improved drawing and stacking blocks: 24-36 months

If babies/toddlers fall out of the range of typical gross and fine motor skills, this would be considered a motor delay. Similar to hypotonia, motor skill delays are often due to an underlying disability, such as structural problems, genetic conditions and other conditions that impact the muscles, such as cerebral palsy or muscular dystrophy. 

There are instances where muscles do not work properly, known as motor dysfunction or motor impairment. 

If a person has motor dysfunction, this means that they have difficulty moving part of their body, usually an arm or leg, or sometimes both. This can cause muscles to become weak, reduce energy or endurance, make it hard to control movements, or lead to paralysis. Motor dysfunction can present with mild symptoms, affecting fine motor skills, whereas more severe motor dysfunction affects gross motor skills. It is often seen in neurological conditions like cerebral palsy, Parkinson’s disease, stroke, and multiple sclerosis. 

Motor dysfunction has a variety of causes depending on the associated disorder, these can be grouped into three primary categories.

Muscular disorders

Where muscles get weaker over time and get worse as you age, such as muscular dystrophy or myasthenia gravis.

Neurological disorders

These are diseases/conditions that disrupt your nervous system due to structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves, which affect the nerves within your muscles and therefore disrupt your movement. This includes disorders as as Parkinson’s disease, multiple sclerosis and cerebral palsy.⁵

Developmental motor disorders

They are a set of mental health conditions that start in childhood and cause significant motor problems in various parts of a child's life, such as developmental coordination disorder and attention deficit hyperactivity disorder, where fine motor skills are particularly affected.

Similar to hypotonia, physical and occupational therapies are popular methods of treatment to help patients complete everyday tasks. As patients with carnosinemia present with motor impairment, it is likely associated with developmental motor disorders as a symptom.

FAQs

Is there a cure for carnosinemia?

There is no cure for carnosinemia, measures can be taken so patients can focus on their symptoms to prevent any further complications and lead a normal life through physical and occupational therapy. It has been suggested that a meat-free vegetarian diet can reduce the amount of carnosine the body has to process, therefore reducing the symptoms. However, this has not been scientifically confirmed.

Summary

Carnosinemia is an extremely rare genetic disorder that is caused by a mutation in the CNDP1 gene. This modified gene reduces the body’s ability to produce carnosinase, that is needed to break down carnosine. This protein metabolism problem can lead to hypotonia (weak muscle tone) and motor dysfunction in infants. Children with hypotonia may appear weak or “floppy” and often experience delays in gross and fine motor skills, such as sitting, crawling, or grasping objects. While there is no cure, physical and occupational therapy can help improve these symptoms.