In neurometabolic and neurogenetic diseases, genetic mutations can affect the brain, spinal cord, nerves, and muscles. Many of these genetic conditions count muscle weakness among their symptoms. In this blog post, we discuss how SequenceMD (and the care teams we collaborate with) evaluate and manage genetic muscle weakness in patients. We also look at some of the neurogenetic conditions that can cause muscle weakness in adults and their clinical symptoms. (As a note, other genetic conditions that do not fall under neurogenetics, including developmental disorders and Ehlers-Danlos syndromes, can also cause muscle weakness.)

How We Evaluate Muscle Weakness

In neurogenetic diseases, muscle weakness usually follows certain patterns. When evaluating a patient, knowing where the muscle weakness is, how fast it started, and what other symptoms are present can help us figure out what’s going on and how to respond.

  • Is the weakness closer to the body (like hips and shoulders) or farther away (like hands and feet)?
  • Is it the same on both sides of the body or different?
  • Did it start suddenly or slowly get worse over time?
  • Are there other symptoms like numbness, changes in reflexes, or muscle twitching?

All of these clues narrow down possible causes. The key question isn’t just “Is there weakness?, but “What pattern of weakness is it?” To gather more information, your care team may also study your gait (how you walk) and test your muscles, reflexes, and ability to do things like climb stairs or rise from a chair. Targeted lab tests, including blood work and MRIs, can provide further details in addition to genetic testing.

Red Flags that Muscle Weakness Has a Genetic Cause

Not all muscle weakness is genetic. However, certain signs make us more likely to suspect a genetic cause for muscle weakness or nerve problems in adults rather than an injury, aging, or another illness. These signs include:

  • Symptoms starting before age 50 without a clear cause
  • Family history of similar symptoms, early disability, or relatives who needed a wheelchair
  • Slow worsening over many years (faster than normal aging)
  • Weakness that is the same on both sides of the body
  • Blood tests that do not show inflammation or autoimmune disease
  • MRI scans showing specific muscles shrinking or being replaced by fat
  • EMG or nerve tests showing long-term muscle or nerve damage without another clear cause

If several of these signs appear together, they point to a need for genetic testing.

Neurogenetic Diseases Linked to Muscle Weakness

Upper Motor Neuron Genetic Conditions

In upper motor neuron (UMN) conditions, the problem is with the brain-to-spinal cord signals, not the muscles themselves. With these conditions, the muscles stiffen, tighten, and may spasm. (Spasticity is the medical term you’ll hear for that.) Muscles usually don’t shrink early on. Walking can become stiff and difficult, and patients have overactive reflexes. Examples of UMN genetic conditions include:

  • Hereditary Spastic Paraplegia (HSP)
  • Primary Lateral Sclerosis (PLS)
  • Leukodystrophy

Lower Motor Neuron Genetic Conditions

In lower motor neuron (LMN) conditions, issues arise in the nerves that carry signals from the spinal cord to the muscles. Because the muscles aren’t getting these signals, they start to shrink. With these conditions, muscles become weak and soft, and reflexes are reduced or missing. The muscle may also twitch under the skin. Genetic LMN conditions include:

  • Spinal Muscular Atrophy (SMA)
  • Spinal and Bulbar Muscular Atrophy (SBMA) (also known as Kennedy Disease)
  • Distal SMA

Combined UMN + LMN Genetic Conditions

These conditions affect both the brain signals and the nerves going to the muscles. This leads to a mix of symptoms, including both weak and stiff muscles. Symptoms progress rapidly and can affect breathing, thinking, or behavior. Examples include:

  • Amyotrophic Lateral Sclerosis (familial ALS)
  • ALS-FTD spectrum (Frontotemporal Dementia)

Genetic Muscle Diseases (Muscular Dystrophies and Myopathies)

In muscular dystrophies and myopathies, the problem occurs in the muscle itself. Signs can include weakness in the hips and shoulders, trouble getting up from the floor, and high creatine kinase (CK) on blood tests. Patients do not normally experience sensory numbness or tingling with these conditions. Genetic muscular dystrophies and myopathies include:

  • Limb-Girdle Muscular Dystrophy
  • Dystrophinopathy (includes Duchenne Muscular Dystrophy)
  • Metabolic myopathies (genetic diseases that impact metabolism)

Peripheral Nerve Diseases (Neuropathy)

In neuropathies, the problem appears in the long nerves that reach the hands and feet, so symptoms start farthest from the body first. Weakness typically begins in the feet and lower legs and can later affect the hands. Numbness, reduced feeling, and balance problems can also occur. High arches in the foot (pes cavus) are common in patients with these conditions. Examples of inherited neuropathies include:

  • Charcot-Marie-Tooth (CMT) disease
  • Hereditary Sensory Neuropathy

Value of Whole Genome Sequencing

Traditional sequential genetic testing only looks at one gene or panel at a time. It is inefficient and becomes expensive as tests pile up. Timing also matters, and, with sequential testing, the patient may not get a diagnosis until intervention is less effective. Whole genome sequencing (WGS), on the other hand, can drastically reduce the diagnostic odyssey for patients with muscle weakness and other concerning symptoms. With WGS, one comprehensive test replaces years of sequential testing.

For patients with red flags for a genetic condition, WGS should be offered early, rather than as a last resort after years of negative testing. In particular, many neurometabolic conditions are treatable but are often missed without WGS. Not only does WGS look at DNA and genetic variants not included in targeted panels, but, as genetic knowledge expands, previously negative WGS data can be evaluated without new tests.

Managing Neurogenetic Muscle Weakness

First, it’s important to know that not all genetic muscle weakness gets worse over time. Some neurogenetic conditions progress very slowly or stabilize entirely. Either way, having a diagnosis can be critical for managing genetic muscle weakness. Even conditions without disease-modifying therapy can benefit from coordinated supportive care, family counseling, and access to clinical trials. We also take care to look at all symptoms and information together to ensure we understand and care for the whole patient, rather than just one part of what’s happening. Depending on the diagnosis, we might recommend:

  • Disease-specific therapy
  • Physical therapy
  • Assistive devices (such as braces or mobility aids)
  • Respiratory and heart monitoring
  • Nutritional support for swallowing difficulties
  • Clinical trial eligibility screening for conditions with emerging therapies

At SequenceMD, we work closely with specialty care providers to help manage patient symptoms and their overall condition. We proactively track all referrals to ensure care is actually delivered, not just recommended. We also work to protect families through cascade testing, as presymptomatic diagnosis in relatives can enable surveillance and early intervention. For more information on how we work with care providers and patients or to discuss seeing a geneticist, contact us anytime.